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  • 51.
    Hamrén, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ericsson, Hans
    Samuelsson, Ola
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function: evidence of interconversion2008In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, no 6, p. 855-863Article in journal (Refereed)
    Abstract [en]

    AIMS

    To develop a mechanistic pharmacokinetic (PK) model for tesaglitazar and its metabolite (an acyl glucuronide) following oral administration of tesaglitazar to subjects with varying renal function, and derive an explanation for the increased plasma exposure of tesaglitazar in subjects with impaired renal function.

    METHODS

    Data were from a 6-week study in subjects with renal insufficiency and matched controls undergoing repeated oral dosing with tesaglitazar (n = 41). Compartmental population PK modelling was employed to describe the PK of tesaglitazar and its metabolite, in plasma and urine, simultaneously. Two hypotheses were tested to investigate the increased exposure of tesaglitazar in subjects with renal functional impairment: tesaglitazar metabolism is correlated with renal function, or metabolite elimination is reduced in renal insufficiency, leading to increased hydrolysis (interconversion) to the parent compound via biliary circulation.

    RESULTS

    The hypothesis for interconversion was best supported by the data. The population PK model included first-order absorption, two-compartment disposition and separate renal (0.027 l h(-1)) and metabolic (1.9 l h(-1)) clearances for tesaglitazar. The model for the metabolite; one-compartment disposition with renal (saturable, V-max = 0.19 mu mol l(-1) and Km = 0.04 mmol l(-1)) and nonrenal clearances (1.2 l h(-1)), biliary secretion (12 h(-1)) to the gut, where interconversion and reabsorption (0.8 h(-1)) of tesaglitazar occurred.

    CONCLUSION

    A mechanistic population PK model for tesaglitazar and its metabolite was developed in subjects with varying degrees of renal insufficiency. The model and data give insight into the likely mechanism (interconversion) of the increased tesaglitazar exposure in renally impaired subjects, and separate elimination and interconversion processes without dosing of the metabolite.

  • 52.
    Hassan, Saadia B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lövborg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    CHS 828 kill tumour cells by inhibiting the nuclear factor-kappa B translocation but unlikely through down-regulation of proteasome2006In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 6B, p. 4431-4436Article in journal (Refereed)
    Abstract [en]

    CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4-pyridylguanidine) has shown promising activity in many preclinical systems and in phase I/II clinical trials. The nuclear transcription factor kappa B (NF-κB) has been identified as a target for CHS 828. The aim of this study was to confirm the inhibitory effect of CHS 828 on NF-κB translocation and to explore its possible effect on the proteasome using 7 cell lines. Translocation of NF-κB from the cytoplasm to the nucleus was analysed using a quantitative cytometric system, ArrayScan®. The activity of the proteasome was assayed by monitoring the hydrolysis of a fluorogenic substrate. In parallel, the in vitro cytotoxic effect of CHS 828 was analyzed using a 72-h microtiter plate-based cytotoxicity assay (FMCA). CHS 828 inhibited NF-κB translocation in the cell lines where it was able to inhibit the tumour cell growth. However, the results did not prove any effect of CHS 828 on proteasome activity when compared to a proteasome inhibitor activity.

  • 53.
    Hassan, Saadia Bashir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    de la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Jonsson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    A hollow fiber model for in vitro studies of cytotoxic compounds: Activity of the cyanoguanidine CHS 8282001In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 12, no 1, p. 33-42Article in journal (Refereed)
    Abstract [en]

    The hollow fiber assay is currently used as an in vivo model for anticancer drug screening in nude mice, but it can also be used as an in vitro model. In the current study, an in vitro hollow fiber model was used to study the effect and mode of induced cell death of a new cyanoguanidine, CHS 828. Human leukemia, adenocarcinoma and lymphoma cell lines as well as primary cultures of human tumor cells from patients with chronic lymphocytic leukemia (CLL) and ovarian cancer (OC) and normal human lymphocytes were cultured in semipermeable hollow fibers. The fibers were incubated for 3 or 14 days prior to CHS 828 exposure for 72 h, followed by determination of living cell density by MTT staining. For cell morphology, using harvested cultures on cytospin slides had technical advantages compared to using paraffin sections of the formalin-fixed fibers. CHS 828 showed higher antitumor activity on CLL and normal human lymphocyte cultures compared to OC cultures, and cell lines cultured 3 days were more sensitive than those cultured 14 days. Morphological examination of CHS 828-treated cultures revealed a mixture of apoptosis and necrosis.

  • 54.
    Hassan, Saadia Bashir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dhar, Sumeer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Sandström, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Arsenau, Dzmitry
    Budnikova, Marina
    Lokot, Igor
    Lobanov, Nikolai
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Cytotoxic activity of a new paclitaxel formulation, Pacliex, in vitro and in vivo2005In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 55, no 1, p. 47-54Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The paclitaxel formulation, Taxol (Bristol-Myers Squibb), is one of the most effective anticancer agents used today. However; it is associated with serious side effects believed to be caused by the Cremophor EL used for its formulation.

    AIM:

    To evaluate the cytotoxic activity of a new paclitaxel formulation, Pacliex (developed by Oasmia Pharmaceutical, Uppsala, Sweden), a mixed micelles preparation in which an amphiphilic synthetic derivative of retinoic acid replaced Cremophor EL/ethanol vehicle.

    METHOD:

    In this study, three model systems were used to evaluate the cytotoxic activity of Pacliex and other paclitaxel preparations. The cytotoxic activities of Pacliex, Taxol and paclitaxel in ethanol were investigated against a panel of ten human tumor cell lines using the fluorometric microculture cytotoxicity assay (FMCA). Low- and high- proliferating in vitro hollow fiber model of two cell lines, the leukemia CCRF-CEM and the myeloma RPMI 8226/S cell lines, were used to assess the cytotoxic activity of the three formulations. The in vivo hollow fiber model of the two cell lines was used for assessment of Pacliex and Taxol activity. The [3-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay was utilized to analyze the in vitro and in vivo hollow fiber data.

    RESULT:

    Pacliex was somewhat more effective than Taxol in the more sensitive cell lines. The activity of Taxol was more pronounced in the resistant cell lines due to an additive effect of the vehicle used. The three formulations showed similar activity in both the low- and high-proliferating in vitro hollow fiber cultures. The in vivo hollow fiber cytotoxic activity of Pacliex was similar to that of Taxol. Putting all the results together, it was found that all the three formulations had similar in vitro and in vivo activity.

    CONCLUSION:

    The three in vitro and in vivo models confirmed the similarity of the cytotoxic activities of Pacliex and Taxol. Considering the above, Pacliex could be an interesting alternative Cremophor EL-free formulation of paclitaxel.

  • 55.
    Hassan, Saadia Bashir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Jonsson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Model for time dependency of the cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action2001In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 299, no 3, p. 1140-1147Article in journal (Refereed)
    Abstract [en]

    CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorometric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation. Patterns of change of drug potency (IC(50)), slope of the concentration-effect curves, and plateau with time were studied. The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC(50) for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC(50) for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC(50) and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death.

  • 56.
    Hauari, Sharifa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Psykisk sjukdom i samband med barnafödande i Stockholms läns landsting2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Postpartum depression (PPD) är ett allvarligt folkhälsoproblem hos nyförlösta kvinnor. Det definieras som en egentlig depression som börjar inom fyra veckor efter förlossningen. Drygt 10-15 % av förlösta kvinnor får PPD efter sin förlossning. Faktorer som kan vara bidragande för utveckling av PPD är ett samspel mellan psykosociala, biologiska och genetiska faktorer. Identifiering av PPD görs med EPDS som är en självskattningsskala och används som ett screeningsinstrument. Syfte: Att undersöka PPD bland kvinnor som föder barn inom SLL som diagnostiseras för psykisk sjukdom eller fått någon typ av behandling för psykisk sjukdom efter förlossningen för att skatta förekomst av PPD. Material och metoder: En deskriptiv tvärsnittsstudie där data uthämtades från VAL-databasen och totalt 99406 förlösta kvinnor analyserades under perioden november 2010-januari 2015. Resultat: Andel diagnostiserat kvinnor för psykisk sjukdom var 0,74 % och 0,71 % nyexpedierades psykofarmaka inom 2 månader efter förlossningen. Förlossningssätt, komplicerat kejsarsnitt (OR=2,35; 95 % CI 2,06 – 2,67) och komplicerad vaginal (OR=1,72; 95 % CI 1,54 – 1,92), socioekonomi, åldern och årstid visade sig vara viktiga variabler för förekomst av PPD. Konklusion: Denna studie visade lägre förekomst av PPD än vad som beskrivit i litteraturen vad gäller diagnosförekomst och expedierade psykofarmaka. Komplikation vid förlossningen vad avser kejsarsnitt eller vaginal förlossning visade vara viktiga prediktorer för förekomst av PPD. Socioekonomisk status respektive ålder uppvisade också statistiskt samband för utveckling av PPD.

  • 57.
    Henningsson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Mechanism-Based Pharmacokinetic and Pharmacodynamic Modelling of Paclitaxel2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Paclitaxel (Taxol®) is now widely used against breast, ovarian and non-small-cell lung cancer. Anticancer agents generally have narrow therapeutic indices, often with myelosuppression (mainly neutropenia) as dose-limiting side effect. A further complicating factor is that paclitaxel when given as Taxol® has a nonlinear pharmacokinetic (PK) behaviour in plasma. Identifying risk groups more sensitive to chemotherapy due to either a PK or pharmacodynamic (PD) interindividual variability is of importance. The aim of the thesis was to develop predictive mechanism-based PK and PD models applicable for paclitaxel.

    PK and PK/PD models were developed for patient data from studies with relatively frequent sampling or sparse sampling schedules. Population analyses were performed using the software NONMEM.

    A pharmacokinetic model describing unbound, total plasma and blood concentrations of paclitaxel from known binding mechanisms was developed and validated. The nonlinear PK in plasma could to a large extent be explained by the micelle forming vehicle Cremophor EL (CrEL) and the unbound drug showed linear PK. Besides a binding component directly proportional to concentrations of CrEL, the model included both linear and nonlinear binding components in plasma and blood. Further, relations between the PK parameters and different demographic factors, including polymorphisms in the cytochrome P450s involved in paclitaxel metabolism, were investigated.

    A semi-physiological PD model for chemotherapy-induced myelosuppression was developed and applied to different anticancer drugs. The model included a self-renewal for proliferating cells, transit compartments describing the delay in observed myelosuppression and a feedback parameter reflecting the effect on the bone marrow from growth factors that can result in an overshoot in white blood cells. The system-related parameters estimated showed consistency across drugs and the difference in the drug-related parameter reflected the relative bone marrow toxicity of the drugs. Relations between demographic factors and the PD parameters were identified.

    The developed mechanism-based models promote a better understanding of paclitaxel PK and PD and may be used as tools in dosing individualisation and in development of dosing strategies for new administration forms and new drugs in the same area.

    List of papers
    1. Mechanism-based pharmacokinetic model for paclitaxel
    Open this publication in new window or tab >>Mechanism-based pharmacokinetic model for paclitaxel
    Show others...
    2001 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 19, no 20, p. 4065-4073Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE

    To create a model based on known mechanisms of paclitaxel distribution that could describe the pharmacokinetics (PK) of total and unbound plasma concentrations, as well as blood concentrations. In addition, to investigate the relationship between exposure, based on unbound and total concentrations, and neutropenia.

    PATIENTS AND METHODS

    Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions. Seven of the patients received combination therapy with doxorubicin or cisplatin. The population PK model was built to fit three types of data simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrophil survival fraction from 19 patients (29 courses in total) to exposure based on unbound and total plasma concentration, respectively.

    RESULTS

    The PK model included a linear three-compartment model for unbound concentration, binding directly proportional to CrEL, linear and nonlinear binding to plasma proteins, and linear and nonlinear binding to blood cells. The threshold model best described the PK/pharmacodynamic (PD) relationship for total concentration. No distinction could be made between the models for unbound drug.

    CONCLUSION

    Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-92973 (URN)11600609 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
    2. Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients
    Open this publication in new window or tab >>Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients
    Show others...
    2003 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 39, no 8, p. 1105-1114Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study was to validate and further develop a mechanism-based population pharmacokinetic model for paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ, USA) based on the knowledge of Cremophor EL (CrEL) micelle entrapment and to evaluate the exposure/toxicity relationships. Paclitaxel (total and unbound) and CrEL concentrations were obtained according to a sparse sampling scheme with on average only 3.5 samples per course from 45 patients with solid tumours who received 3-hour infusions of paclitaxel (final dose range 112-233 mg/m(2)). The present data were predicted well by the mechanism-based model. In addition, bilirubin and body size were found to be significant as covariates. A change in body surface area (BSA) of 0.1 m(2) typically caused a change in clearance (CL) of 22.3 l/h and an increase in bilirubin of 10 microM typically caused a decrease in CL of 41 l/h. Toxicity was best described by a threshold model. In conclusion, even with a sparse sampling scheme, the same mechanism-based binding components as in the previously developed model could be identified. Once the CrEL and total paclitaxel plasma concentrations are known, the unbound concentrations, which are more closely related to the haematological toxicity, can be predicted.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-92974 (URN)10.1016/S0959-8049(03)00126-6 (DOI)12736110 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
    3. Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel.
    Open this publication in new window or tab >>Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel.
    Show others...
    2005 (English)In: Clin Cancer Res, ISSN 1078-0432, Vol. 11, no 22, p. 8097-104Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-75576 (URN)16299241 (PubMedID)
    Available from: 2006-03-08 Created: 2006-03-08 Last updated: 2011-07-05
    4. Population Pharmacokinetic Model for Cremophor EL
    Open this publication in new window or tab >>Population Pharmacokinetic Model for Cremophor EL
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-92976 (URN)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2011-03-01
    5. Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs
    Open this publication in new window or tab >>Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs
    Show others...
    2002 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 20, no 24, p. 4713-4721Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE:

    To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs.

    PATIENTS AND METHODS:

    Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software.

    RESULTS:

    For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs.

    CONCLUSION:

    This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-92977 (URN)10.1200/JCO.2002.02.140 (DOI)12488418 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
    6. Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs
    Open this publication in new window or tab >>Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs
    Show others...
    2006 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 12, no 18, p. 5481-5490Article in journal (Refereed) Published
    Abstract [en]

    Purpose: Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs.

    Experimental Design: Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made.

    Results: A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and alpha(1)-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction.

    Conclusions: These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-100514 (URN)10.1158/1078-0432.CCR-06-0815 (DOI)000240714400033 ()17000683 (PubMedID)
    Available from: 2009-04-07 Created: 2009-04-01 Last updated: 2018-01-13Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 58. Henningsson, Anja
    et al.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Viganò, Lucia
    Gianni, Luca
    Verweij, Jaap
    Sparreboom, Alex
    Mechanism-based pharmacokinetic model for paclitaxel2001In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 19, no 20, p. 4065-4073Article in journal (Refereed)
    Abstract [en]

    PURPOSE

    To create a model based on known mechanisms of paclitaxel distribution that could describe the pharmacokinetics (PK) of total and unbound plasma concentrations, as well as blood concentrations. In addition, to investigate the relationship between exposure, based on unbound and total concentrations, and neutropenia.

    PATIENTS AND METHODS

    Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions. Seven of the patients received combination therapy with doxorubicin or cisplatin. The population PK model was built to fit three types of data simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrophil survival fraction from 19 patients (29 courses in total) to exposure based on unbound and total plasma concentration, respectively.

    RESULTS

    The PK model included a linear three-compartment model for unbound concentration, binding directly proportional to CrEL, linear and nonlinear binding to plasma proteins, and linear and nonlinear binding to blood cells. The threshold model best described the PK/pharmacodynamic (PD) relationship for total concentration. No distinction could be made between the models for unbound drug.

    CONCLUSION

    Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations.

  • 59.
    Henningsson, Anja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Sparreboom, Alex
    Loos, Walter J.
    Verweij, Jaap
    Silvander, Mats
    Karlsson, Mats O.
    Population Pharmacokinetic Model for Cremophor ELManuscript (Other academic)
  • 60.
    Henningsson, Anja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Sparreboom, Alex
    Sandström, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Freijs, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bergh, Jonas
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients2003In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 39, no 8, p. 1105-1114Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to validate and further develop a mechanism-based population pharmacokinetic model for paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ, USA) based on the knowledge of Cremophor EL (CrEL) micelle entrapment and to evaluate the exposure/toxicity relationships. Paclitaxel (total and unbound) and CrEL concentrations were obtained according to a sparse sampling scheme with on average only 3.5 samples per course from 45 patients with solid tumours who received 3-hour infusions of paclitaxel (final dose range 112-233 mg/m(2)). The present data were predicted well by the mechanism-based model. In addition, bilirubin and body size were found to be significant as covariates. A change in body surface area (BSA) of 0.1 m(2) typically caused a change in clearance (CL) of 22.3 l/h and an increase in bilirubin of 10 microM typically caused a decrease in CL of 41 l/h. Toxicity was best described by a threshold model. In conclusion, even with a sparse sampling scheme, the same mechanism-based binding components as in the previously developed model could be identified. Once the CrEL and total paclitaxel plasma concentrations are known, the unbound concentrations, which are more closely related to the haematological toxicity, can be predicted.

  • 61. Holford, N
    et al.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Time for quantitative clinical pharmacology: a proposal for a pharmacometrics curriculum2007In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 82, no 1, p. 103-105Article in journal (Refereed)
    Abstract [en]

    A formal training program in pharmacometrics is essential to train clinical pharmacology scientists. A proposal is made for a pharmacometrics curriculum. The curriculum has components at the undergraduate, graduate and postgraduate levels.

  • 62.
    Hooker, Andrew C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Staatz, Christine E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Conditional weighted residuals (CWRES): a model diagnostic for the FOCE method2007In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 24, no 12, p. 2187-2197Article in journal (Refereed)
    Abstract [en]

    Purpose  Population model analyses have shifted from using the first order (FO) to the first-order with conditional estimation (FOCE) approximation to the true model. However, the weighted residuals (WRES), a common diagnostic tool used to test for model misspecification, are calculated using the FO approximation. Utilizing WRES with the FOCE method may lead to misguided model development/evaluation. We present a new diagnostic tool, the conditional weighted residuals (CWRES), which are calculated based on the FOCE approximation. Materials and Methods  CWRES are calculated as the FOCE approximated difference between an individual’s data and the model prediction of that data divided by the root of the covariance of the data given the model. Results  Using real and simulated data the CWRES distributions behave as theoretically expected under the correct model. In contrast, in certain circumstances, the WRES have distributions that greatly deviate from the expected, falsely indicating model misspecification. CWRES/WRES comparisons can also indicate if the FOCE estimation method will improve the results of an FO model fit to data. Conclusions  Utilization of CWRES could improve model development and evaluation and give a more accurate picture of if and when a model is misspecified when using the FO or FOCE methods.

  • 63.
    Hooker, Andrew C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ten Tije, A J
    Carducci, M A
    Weber, J
    Garrett-Mayer, E
    Gelderblom, H
    McGuire, W P
    Verweij, J
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Baker, S D
    Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: incorporating cytochrome P4503A activity measurements2008In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 84, no 1, p. 111-118Article in journal (Refereed)
    Abstract [en]

    The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m(2) was administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in LF tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 l/h) and more variable in patients with LF abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may lie in identifying safe docetaxel doses for patients with LF abnormalities.

  • 64.
    Hovstadius, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Skov, Torsten
    Kissmeyer, Ann-Marie
    Krasilnikoff, Klaus
    Bergh, Jonas
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Lönnebo, Anna
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    A Phase I Study of CHS 828 in Patients with Solid Tumor Malignancy2002In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 8, no 9, p. 2843-2850Article in journal (Refereed)
    Abstract [en]

    CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1–5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 ± 1.3 h and half-life was 2.1 ± 0.52 h (mean ± SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.

  • 65.
    Ibrahim, Hima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Administrering av koffeincitrat till för tidigt födda barn med apné2018Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Administration of caffeine citrate to newborns with apnea

    Background: For over 40 years, caffeine has been the best medicine in the treatment of neonatal apnea. It is a nonspecific inhibitor of adenosine receptors of subtype A1- and A2Aaa. The commercial product is an orphan drug named Peyona, which is usually administrated intravenously through intermittent infusion. This is both time consuming and expensive, which leads us to the conclusion to study the ability of administrating it as an intravenous injection.

    Objective: To investigate the possibilities to administrate caffeine citrate as an injection instead of an intermittent infusion in newborns with apnea.

    Materials and Methods: Non-clinical measurements of the concentration and amount of caffeine that reaches the patient (dose: 15 mg caffeine citrate) after intermittent infusion of 15 minutes were performed by using UV-vis Druglog apparatus for two types of infusion systems; A+C (lowest dead space) and A+B+C (highest dead space). In addition, a survey and unstructured interviews touching upon the administration of caffeine citrate were conducted as well as a simplified cost-value evaluation.

    Results: The amount of caffeine citrate detected after 15 minutes was 14.3 mg (95%CI 14.0 – 14.6) respectively 10.2 mg (95%CI 8.9 – 11.4) for system A+C and A+B+C. The majority of the nurses (n=15) of the total n=18 claimed to administrate Peyona according to existing guidelines from the Swedish national formulary for pediatric drugs, known as ePed. The annual cost-savings for Peyona 20 mg/mL would be 180,000 SEK if Peyona is given as an intravenous injection at the Astrid Lindgren Childen’s Hospital.

    Conclusion: The full dose of caffeine citrate given did not reach the patient after 15 minutes of infusion as expected. An amount of caffeine citrate always came out with the flush samples given for system A+C and A+B+C. Therefore, new guidelines for Peyona 20 mg/mL is now available on ePed to administrate Peyona as an intravenous injection followed by a slowly given flush over ten minutes. 

  • 66.
    Jansson, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ashton, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simultaneous enantiospecific separation and quantitation of mephenytoin and its metabolites nirvanol and 4'-hydroxymephenytoin in human plasma by liquid chromatography2003In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 791, no 1-2, p. 179-191Article in journal (Refereed)
    Abstract [en]

    A high-performance liquid chromatographic method for the enantiospecific quantitation of S- and R-mephenytoin and its metabolites S- and R-nirvanol and S- and R-4'-hydroxymephenytoin in plasma is described. The compounds were separated using a reversed-phase C(2) column in tandem with a chiral alpha(1)-acid glycoprotein column and were detected using ultraviolet detection at 205 nm. The lower limit of quantification was 10 ng/ml for all compounds using 0.5 ml human plasma (intra-day coefficient of variation <13%, accuracy <+/-20%). The method was validated for human plasma in the concentration range 10-2000 ng/ml for each of the six compounds. The method allows for the simultaneous characterisation of the metabolic capacity of two human drug-metabolising enzymes, CYP2C19 and CYP2B6, and may be used when investigating polymorphisms or changes in activity of these two enzymes.

  • 67.
    Jargur, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Uteblivna dostillfällen vid kirurgkliniken på Danderyds sjukhus AB: en deskriptiv studie av förekomst och orsak till att signerade läkemedel inte administreras2016Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Uteblivna doser utgör ett globalt och vanligt förekommande problem i slutenvård. I utländska material har problematiken förknippats med patientsäkerhetsrisker och i extremfall till dödsfall. I svensk sjukvård saknas i stor utsträckning kunskap om problemet. Syfte: Kartläggning av andel signerade uteblivna doser, problemets fördelning till olika läkemedelsgrupper samt angivna orsaker till uteblivna doser för att bedöma hur vanligt detta problem är vid kirurgkliniken på Danderyds sjukhus. Metod & Material: En kvantitativ deskriptiv studie med kvalitativt inslag under 25 dagar vid kirurgkliniken på Danderyds sjukhus. Information om läkemedelsdoser inhämtades från journalsystemet TakeCare för patienter som vårdades under studietiden. Kvalitativa data baserades på en semistrukturerad intervju av sex sjuksköterskor. Resultat: Fyrahundra patienter bidrog med totalt 5867 doser, varav 13,1% inte administrerades under vårdtiden. Läkemedelsgrupper med högst antal uteblivna doser var analgetika (18,5%), kardiovaskulära medel (8,7%) och medel vid obstruktiva luftvägssjukdomar (7,0%). De huvudsakliga orsakerna till dessa var ”patienten fastar” (21,0%), ”medicinska/omvårdnadsmässiga skäl” (17,4%), ”patienten vill ej ha läkemedel” (12,3%) samt ”läkemedel ej tillgängligt på avdelningen” (11,5%). För 26,2% av uteblivna doser angavs ingen orsak och de intervjuade sjuksköterskorna medgav att orsaken då oftast var underförstådd. Konklusion: Drygt var tionde signerad läkemedelsdos för regelbunden användning administrerades aldrig under vårdtiden. Baserat på de orsaker som angavs var det ofta rimligt att doserna inte administrerades. Dock var orsaken till mer än var tionde utebliven dos att läkemedlet ej fanns tillgängligt på avdelningen. Detta upplevdes av sjuksköterskorna som en patientsäkerhetsrisk.  

  • 68.
    Jauslin, Petra M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Silber, Hanna E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Frey, Nicolas
    Gieschke, Ronald
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jorga, Karin
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    An integrated glucose-insulin model to describe oral glucose tolerance test data in type 2 diabetics2007In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 10, p. 1244-1255Article in journal (Refereed)
    Abstract [en]

    An integrated model for the glucose-insulin system describing oral glucose tolerance test data was developed, extending on a previously introduced model for intravenous glucose provocations. Model extensions comprised the description of glucose absorption by a chain of transit compartments with a mean transit time of 35 minutes, a bioavailability of 80%, and a representation of the incretin effect, expressed as a direct effect of the glucose absorption rate on insulin secretion. The ability of the model to predict the incretin effect was assessed by simulating the observed difference in insulin response following an oral glucose tolerance test compared with an isoglycemic glucose infusion mimicking an oral glucose tolerance test profile. The extension of the integrated glucose-insulin model to gain information from oral glucose tolerance test data considerably expands its range of applications because the oral glucose tolerance test is one of the most common glucose challenge experiments for assessing the efficacy of hypoglycemic agents in clinical drug development.

  • 69.
    Jonsson, E Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Antila, Saila
    McFadyen, Lynn
    Lehtonen, Lasse
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Population pharmacokinetics of levosimendan in patients with congestive heart failure2003In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 55, no 6, p. 544-551Article in journal (Refereed)
    Abstract [en]

    AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.

  • 70.
    Jonsson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hassan, Saadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Freijs, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hansen, Klaus
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats2000In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 46, no 6, p. 493-500Article in journal (Refereed)
    Abstract [en]

    PURPOSE

    Based on the previously published hollow-fibre assay mainly used for early in vivo anticancer drug screening, we wanted to develop an extended hollow-fibre model in which antitumour activity, haematological toxicity and pharmacokinetics could be studied in the same animal.

    METHOD

    The breast cancer cell lines MDA-MB-231 and MCF-7 were cultured in semipermeable hollow fibres. The fibres were implanted subcutaneously into immunocompetent male Sprague Dawley rats, and the rats were treated with 5-fluorouracil (5-FU, 125 mg/kg), epirubicin (EPI, 10 mg/kg) or cyclophosphamide (CP, 120 mg/kg) intraperitoneally, the new cyanoguanidine CHS 828 (375 mg/kg or 75 mg/kg x 5) orally, or vehicle only. After 6 days the fibres were retrieved and the cell density was evaluated. Haematological parameters were monitored and two to four samples per animal were drawn to determine the pharmacokinetic parameters in NONMEM.

    RESULTS

    Drug treatment had generally low effects on the tumour cells. Of the standard drugs (5-FU, EPI and CP), only CP exerted a statistically significant antiproliferative effect. CHS 828 had only a minor effect as a single dose, but divided into five daily doses had a pronounced effect on both cell lines. 5-FU, EPI and CP all caused a marked decrease in leucocytes, platelets and haemoglobin, while CHS 828 did not seem to affect these parameters. The pharmacokinetics of 5-FU and EPI were in accordance with previously established pharmacokinetic models. The pharmacokinetics of CP and CHS 828 were both described by one-compartment models.

    CONCLUSIONS

    This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal using the hollow-fibre model.

  • 71.
    Jonsson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jonsson, E. Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Bois, Frédéric Y.
    Marshall, Scott
    The application of a Bayesian approach to the analysis of a complex, mechanistically based model2007In: Journal of Biopharmaceutical Statistics, ISSN 1054-3406, E-ISSN 1520-5711, Vol. 17, no 1, p. 65-92Article in journal (Refereed)
    Abstract [en]

    The Bayesian approach has been suggested as a suitable method in the context of mechanistic pharmacokinetic-pharmacodynamic (PK-PD) modeling, as it allows for efficient use of both data and prior knowledge regarding the drug or disease state. However, to this day, published examples of its application to real PK-PD problems have been scarce. We present an example of a fully Bayesian re-analysis of a previously published mechanistic model describing the time course of circulating neutrophils in stroke patients and healthy individuals. While priors could be established for all population parameters in the model, not all variability terms were known with any degree of precision. A sensitivity analysis around the assigned priors used was performed by testing three different sets of prior values for the population variance terms for which no data were available in the literature: “informative”, “semi-informative”, and “noninformative”, respectively. For all variability terms, inverse gamma distributions were used. It was possible to fit the model to the data using the “informative” priors. However, when the “semi-informative” and “noninformative” priors were used, it was impossible to accomplish convergence due to severe correlations between parameters. In addition, due to the complexity of the model, the process of defining priors and running the Markov chains was very time-consuming. We conclude that the present analysis represents a first example of the fully transparent application of Bayesian methods to a complex, mechanistic PK-PD problem with real data. The approach is time-consuming, but enables us to make use of all available information from data and scientific evidence. Thereby, it shows potential both for detection of data gaps and for more reliable predictions of various outcomes and “what if” scenarios.

  • 72. Juhlin, Tord
    et al.
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Höglund, Peter
    Cyclooxygenase inhibition causes marked impairment of renal function in elderly subjects treated with diuretics and ACE-inhibitors2005In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 7, no 6, p. 1049-1056Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Treatment with angiotensin-converting enzyme (ACE)-inhibitors is known to cause an initial reduction in glomerular filtration rate (GFR) in patients with congestive heart failure. The long-term beneficial effects of ACE-inhibitors in these patients can be counteracted by cyclooxygenase-inhibitors. AIMS: To quantify the negative renal effects of the cyclooxygenase-inhibitor diclofenac in elderly healthy subjects and to assess how treatment with an ACE-inhibitor, after activation of the renin-angiotensin system, influences these renal effects. METHODS: Fourteen elderly, healthy subjects received oral diclofenac and placebo in a double-blind cross-over fashion. The study was divided in two parts; in part one, subjects received no pre-treatment and in part two, the subjects were given pre-treatment with bendroflumethiazide and enalapril in order to activate the renin-angiotensin system. RESULTS: Diclofenac induced significant (p<0.05) decreases in GFR, urine flow, excretion rates of sodium and potassium, electrolyte clearance, osmolality clearance and free water clearance both with and without renin-angiotensin system activation. Least square means (95% CI) of all observations during the first 6 h after dosing showed that diclofenac caused a reduction in GFR from 71 (64-78) to 59 (52-66) ml/min. After pre-treatment, diclofenac further reduced GFR from 60 (52-67) to 48 (40-55) ml/min. After diclofenac administration, urine flow fell from 7.4 (6.4-8.3) to 5.1 (4.2-6.1) ml/min, after pre-treatment, diclofenac gave a further reduction from 4.1 (3.1-5.1) to 2.2 (1.3-3.2) ml/min. More than half of the reductions were caused by the pre-treatment. CONCLUSION: Renal function in elderly, healthy subjects is impaired after acute intake of diclofenac. This impairment is observed both with and without activation of the renin-angiotensin system and ACE-inhibitor treatment but is more pronounced after pre-treatment.

  • 73.
    Juutinen, Niko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Immunmodulerande biologiska läkemedel2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Immunmodulerande biologiska läkemedel

    Niko Juutinen

    Margareta Hammarlund-Udenaes, Institutionen för farmaceutisk biovetenskap/ avdelningen för farmakokinetik och läkemedelsterapi, 15 hp. Examinator Elisabet Nielsen

    Introduktion: Biologiska läkemedels (BLM) aktiva substanser är tillverkade av eller har renats fram ur biologiskt materiel. Den aktiva substansen ska ha en heterogen struktur. Cytokiner är stor grupp signalsubstanser som deltar i parakrin kommunikation. Immunoglobuliner är antikroppar med affinitet för antigener. Förvärvade immunsystemet ansvarar för antikroppsbildning och igenkännandet av antigener. MAbs framställs med rekombinant DNA-teknik och beroende på hur stor andel av mAbs har human proteinstruktur respektive xenogent ger det annorlunda klinisk användbarhet och biverkningsrisk. Syfte: Svara på följande frågeställningar: Hur har användning och kostnad av immunmodulerande BLM förändrats i Sverige under perioden på 2009-2013? Hur ser biverkningsprofilerna ut för immunmodulerande BLM och vad kan göras för att minska risker för biverkningar? Har antalet biverkningrapporteringar av immunmodulerande BLM förändrats under perioden på 2009-2013? Hur ser framtiden ut för BLM? Material och metoder: Litteraturstudien utfördes genom att ta del av litteratur om immunsystemets fysiologi och funktion, immunologi, mikrobiologi och forskning inom området BLM. Vetenskapliga artiklar söktes från PubMed och ub.uu.se. Mailkontakt med Läkemedelsverket togs angående biverkningsstatistik och framtiden av immunmodulerande BLM. Kostnadsuppgifter och antalet patienter av immunmodulerande behandlingar söktes fram från Socialstyrelsens årliga rapporter av läkemedelsstatistik och analyser och Socialstyrelsens statistikdatabas. Resultat: Immunsuppressiva och immunstimulerande läkemedlen utgör stora kostnader inom läkemedelsförmånssystemet och sluten vård. TNF-alfa hämmarna mot RA och psoriasis är de vanligaste BLM. Vanligaste biverkningarna av BLM är infektioner, hudreaktioner, feber och allergiska reaktioner. Premedicinering med antihistaminer och paracetamol, välutbildat sjukvårdspersonal och välinformerade patienter är sätt att minska biverkningar. Många nya BLM är under olika steg av kliniska utvecklingsfaser. Konklusion: Biologiska läkemedel är viktiga läkemedel mot allvarliga sjukdomar, men med allvarliga biverkningar och höga kostnader. I framtiden kommer biologiska läkemedel få en ännu större roll inom sjukvården.

  • 74.
    Jönsson, Siv
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Estimation of Dosing Strategies for Individualisation2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    To increase the proportion of patients with successful drug treatment, dose individualisation on the basis of one or several patient characteristics, a priori individualisation, and/or on the basis of feedback observations from the patient following an initial dose, a posteriori individualisation, is an option. Efficient tools in optimising individualised dosing strategies are population models describing pharmacokinetics (PK) and the relation between pharmacokinetics and pharmacodynamics (PK/PD).

    Methods for estimating optimal dosing strategies, with a discrete number of doses, for dose individualisation a priori and a posteriori were developed and explored using simulated data. The methods required definitions of (i) the therapeutic target, i.e. the value of the target variable and a risk function quantifying the seriousness of deviation from the target, (ii) a population PK/PD model relating dose input to the target variable in the patients to be treated, and (iii) distributions of relevant patient factors. Optimal dosing strategies, in terms of dose sizes and individualisation conditions, were estimated by minimising the overall risk. Factors influencing the optimal dosing strategies were identified. Consideration of those will have implications for study design, data collection, population model development and target definition.

    A dosing strategy for a priori individualisation was estimated for NXY-059, a drug under development. Applying the estimated dosing strategy in a clinical study resulted in reasonable agreement between observed and expected outcome, supporting the developed methodology.

    Estimation of a dosing strategy for a posteriori individualisation for oxybutynin, a drug marketed for the treatment of overactive bladder, illustrated the implementation of the method when defining the therapeutic target in terms of utility and responder probability, that is, as a combination of the desired and adverse effects.

    The proposed approach provides an estimate of the maximal benefit expected from individualisation and, if individualisation is considered clinically superior, the optimal conditions for individualisation. The main application for the methods is in drug development where the methods can be generally employed in the establishment of dosing strategies for individualisation with relevant extensions regarding population model complexity and individualisation conditions.

    List of papers
    1. A rational approach for selection of optimal covariate-based dosing strategies
    Open this publication in new window or tab >>A rational approach for selection of optimal covariate-based dosing strategies
    2003 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 73, no 1, p. 7-19Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND

    At present, there is no rational approach for choosing a dosing strategy for individualization based on a covariate. An approach to use in establishment of an a priori dosing strategy for individualization is presented. Factors influencing the choice of such a dosing strategy are identified.

    METHODS

    The approach requires definition of the following: target variable, seriousness of deviations from the target (ie, risk function), population model, covariate distributions, and constraints. Minimizing the total risk yields an optimal dosing strategy, estimated as dose sizes for different subpopulations and covariate cutoff values at which doses are increased or decreased. The method was illustrated with the use of simulated and real drug examples for the situation in which clearance is related to creatinine clearance.

    RESULTS

    The estimated optimal cutoff(s) paralleled the median creatinine clearance in the population. The extent of variability in clearance explained by creatinine clearance was the main factor influencing the optimal ratios between adjacent dose sizes. An optimal dosing strategy was possible to estimate for the real drug.

    CONCLUSIONS

    The method is simple to perform, although one difficulty lies in defining the target variable and risk function. Our results imply that commonly used constraints in dosing strategies based on renal function (ie, dose ratio of 2 and predetermined cutoffs) are nonoptimal in the sense we propose. Because an optimal dosing strategy may not be practical to use, the therapeutic cost that would result with any constraint can be assessed by comparison of the outcome after the desired and the optimal strategy.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91732 (URN)10.1067/mcp.2003.2 (DOI)12545139 (PubMedID)
    Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2017-12-14Bibliographically approved
    2. Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke
    Open this publication in new window or tab >>Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke
    Show others...
    2005 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 44, no 8, p. 863-878Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND AND OBJECTIVES

    NXY-059 (disufenton sodium, Cerovive, a nitrone with neuroprotective and free radical trapping properties (in experimental stroke) is under development for the treatment of acute stroke. The objectives of this study were to develop a population pharmacokinetic model for NXY-059 in acute stroke patients and to estimate individualised dosing strategies for NXY-059 using preclinical pharmacological and clinical pharmacokinetic information and knowledge of characteristics of the patient population.

    METHODS

    NXY-059 was given as a continuous intravenous infusion for 72 hours, including a 1-hour loading infusion. Maintenance infusion rates were individualised based on creatinine clearance (CL(CR)). Population pharmacokinetic models were derived using NONMEM software. Optimal dosing strategies, individualised based on CL(CR) or bodyweight, were estimated using the population pharmacokinetic models, empirical covariate distributions relevant for the target population, and a target definition. Dosing strategies were selected based on target fulfillment criteria and parsimony.

    PATIENTS

    Pharmacokinetic data from 179 patients with acute ischaemic or haemorrhagic stroke, included in two clinical studies, were used for the analyses. Patients were aged 34-92 years with varying degrees of renal impairment (estimated CL(CR) 20-143 mL/min).

    MAIN OUTCOME MEASURES AND RESULTS

    The final population model based on data from both studies comprised a two-compartment model with unexplained interpatient variability for clearance (23% coefficient of variation [CV]) and central volume of distribution (40% CV). Part of the variability in clearance and volume of distribution was explained by CL(CR) and bodyweight, respectively. Typical clearance was estimated to 4.54 L/h in a patient with CL(CR) of 70 mL/min. The preferred dosing strategy for NXY-059 comprised an initial loading infusion (the same for all patients) followed by an individualised maintenance infusion on the basis of CL(CR) (three dosing categories) with cut-off values (at which infusion rates are incremented or decremented) of 50 and 80 mL/min.

    CONCLUSION

    The results illustrate how an individualised dosing strategy, given a pharmacokinetic target, for NXY-059 was successfully optimised through estimation using the increasing pharmacokinetic and pharmacodynamic knowledge during a clinical drug development programme. The chosen dosing strategy of NXY-059 provides an easily adapted treatment regimen for acute stroke, resulting in early achievement of target plasma concentrations.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91733 (URN)16029070 (PubMedID)
    Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2017-12-14Bibliographically approved
    3. Factors influencing the choice of optimal individualized dosing strategies targeting a drug concentration or effect
    Open this publication in new window or tab >>Factors influencing the choice of optimal individualized dosing strategies targeting a drug concentration or effect
    2004 (English)In: AAPS PharmSci, ISSN 1522-1059Article in journal (Refereed) Submitted
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91734 (URN)
    Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2017-12-14Bibliographically approved
    4. Estimation of dosing strategies aiming at maximizing utility or responder probability, using oxybutynin as an example drug
    Open this publication in new window or tab >>Estimation of dosing strategies aiming at maximizing utility or responder probability, using oxybutynin as an example drug
    2005 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, no 1, p. 123-132Article in journal (Refereed) Published
    Abstract [en]

    Methods for optimizing dosing strategies for individualization with a limited number of discrete doses, in terms of maximizing the expected utility of treatment or responder probability, are presented. The optimality criteria require models for both beneficial and adverse effects that are part of the utility definition and published population models describing those effects for oxybutynin (urge urinary incontinence episodes per week and severity of dry mouth, respectively) were used for illustration. Dosing strategies with two dosing categories were defined in terms of sizes of the daily doses (low and high dose) and the proportion of patients that can be expected to be preferentially treated at the low dose level. Utility and responder definitions were varied to investigate the influence on the resulting dosing strategy. By minimizing a risk function, describing the seriousness of deviations from the predefined target, optimal dosing strategies were estimated using mixture models in NONMEM. The estimated dose ranges for oxybutynin were similar to those recommended. The optimal individualization conditions were dependent on the definitions of responder and utility. The predicted gain of individualization given utility and responder definitions used was greater, when a responder criteria was maximized compared with maximizing utility.

    Keywords
    Dosing strategy, Individualization, Utility and responder definition, Optimization, Risk–benefit, NONMEM
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91735 (URN)10.1016/j.ejps.2005.02.004 (DOI)15854808 (PubMedID)
    Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2017-12-14Bibliographically approved
    5. Estimating bias in population parameters for some models for repeated measures ordinal data using NONMEM or NLMIXED
    Open this publication in new window or tab >>Estimating bias in population parameters for some models for repeated measures ordinal data using NONMEM or NLMIXED
    2004 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 31, no 4, p. 299-320Article in journal (Refereed) Published
    Abstract [en]

    The application of proportional odds models to ordered categorical data using the mixed-effects modeling approach has become more frequently reported within the pharmacokinetic/pharmacodynamic area during the last decade. The aim of this paper was to investigate the bias in parameter estimates, when models for ordered categorical data were estimated using methods employing different approximations of the likelihood integral; the Laplacian approximation in NONMEM (without and with the centering option) and NLMIXED, and the Gaussian quadrature approximations in NLMIXED. In particular, we have focused on situations with non-even distributions of the response categories and the impact of interpatient variability. This is a Monte Carlo simulation study where original data sets were derived from a known model and fixed study design. The simulated response was a four-category variable on the ordinal scale with categories 0, 1, 2 and 3. The model used for simulation was fitted to each data set for assessment of bias. Also, simulations of new data based on estimated population parameters were performed to evaluate the usefulness of the estimated model. For the conditions tested, Gaussian quadrature performed without appreciable bias in parameter estimates. However, markedly biased parameter estimates were obtained using the Laplacian estimation method without the centering option, in particular when distributions of observations between response categories were skewed and when the interpatient variability was moderate to large. Simulations under the model could not mimic the original data when bias was present, but resulted in overestimation of rare events. The bias was considerably reduced when the centering option in NONMEM was used. The cause for the biased estimates appears to be related to the conditioning on uninformative and uncertain empirical Bayes estimate of interindividual random effects during the estimation, in conjunction with the normality assumption.

    Keywords
    NONMEM, NLMIXED, SAS, Laplacian, Gaussian quadrature, maximum likelihood estimation, ordered categorical, proportional odds model, bias in parameter estimates
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91736 (URN)10.1023/B:JOPA.0000042738.06821.61 (DOI)15563005 (PubMedID)
    Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2017-12-14
    Download full text (pdf)
    FULLTEXT01
  • 75.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Cheng, Yi-Fang
    Edenius, Charlotte
    Lees, Kennedy R.
    Odergren, Tomas
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke2005In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 44, no 8, p. 863-878Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES

    NXY-059 (disufenton sodium, Cerovive, a nitrone with neuroprotective and free radical trapping properties (in experimental stroke) is under development for the treatment of acute stroke. The objectives of this study were to develop a population pharmacokinetic model for NXY-059 in acute stroke patients and to estimate individualised dosing strategies for NXY-059 using preclinical pharmacological and clinical pharmacokinetic information and knowledge of characteristics of the patient population.

    METHODS

    NXY-059 was given as a continuous intravenous infusion for 72 hours, including a 1-hour loading infusion. Maintenance infusion rates were individualised based on creatinine clearance (CL(CR)). Population pharmacokinetic models were derived using NONMEM software. Optimal dosing strategies, individualised based on CL(CR) or bodyweight, were estimated using the population pharmacokinetic models, empirical covariate distributions relevant for the target population, and a target definition. Dosing strategies were selected based on target fulfillment criteria and parsimony.

    PATIENTS

    Pharmacokinetic data from 179 patients with acute ischaemic or haemorrhagic stroke, included in two clinical studies, were used for the analyses. Patients were aged 34-92 years with varying degrees of renal impairment (estimated CL(CR) 20-143 mL/min).

    MAIN OUTCOME MEASURES AND RESULTS

    The final population model based on data from both studies comprised a two-compartment model with unexplained interpatient variability for clearance (23% coefficient of variation [CV]) and central volume of distribution (40% CV). Part of the variability in clearance and volume of distribution was explained by CL(CR) and bodyweight, respectively. Typical clearance was estimated to 4.54 L/h in a patient with CL(CR) of 70 mL/min. The preferred dosing strategy for NXY-059 comprised an initial loading infusion (the same for all patients) followed by an individualised maintenance infusion on the basis of CL(CR) (three dosing categories) with cut-off values (at which infusion rates are incremented or decremented) of 50 and 80 mL/min.

    CONCLUSION

    The results illustrate how an individualised dosing strategy, given a pharmacokinetic target, for NXY-059 was successfully optimised through estimation using the increasing pharmacokinetic and pharmacodynamic knowledge during a clinical drug development programme. The chosen dosing strategy of NXY-059 provides an easily adapted treatment regimen for acute stroke, resulting in early achievement of target plasma concentrations.

  • 76.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    A rational approach for selection of optimal covariate-based dosing strategies2003In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 73, no 1, p. 7-19Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    At present, there is no rational approach for choosing a dosing strategy for individualization based on a covariate. An approach to use in establishment of an a priori dosing strategy for individualization is presented. Factors influencing the choice of such a dosing strategy are identified.

    METHODS

    The approach requires definition of the following: target variable, seriousness of deviations from the target (ie, risk function), population model, covariate distributions, and constraints. Minimizing the total risk yields an optimal dosing strategy, estimated as dose sizes for different subpopulations and covariate cutoff values at which doses are increased or decreased. The method was illustrated with the use of simulated and real drug examples for the situation in which clearance is related to creatinine clearance.

    RESULTS

    The estimated optimal cutoff(s) paralleled the median creatinine clearance in the population. The extent of variability in clearance explained by creatinine clearance was the main factor influencing the optimal ratios between adjacent dose sizes. An optimal dosing strategy was possible to estimate for the real drug.

    CONCLUSIONS

    The method is simple to perform, although one difficulty lies in defining the target variable and risk function. Our results imply that commonly used constraints in dosing strategies based on renal function (ie, dose ratio of 2 and predetermined cutoffs) are nonoptimal in the sense we propose. Because an optimal dosing strategy may not be practical to use, the therapeutic cost that would result with any constraint can be assessed by comparison of the outcome after the desired and the optimal strategy.

  • 77.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    A rational approach for selection of optimal covariate-based dosing strategies2003In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 73, no 1, p. 7-19Article in journal (Other academic)
    Abstract [en]

    BACKGROUND: At present, there is no rational approach for choosing a dosing strategy for individualization based on a covariate. An approach to use in establishment of an a priori dosing strategy for individualization is presented. Factors influencing the choice of such a dosing strategy are identified. METHODS: The approach requires definition of the following: target variable, seriousness of deviations from the target (ie, risk function), population model, covariate distributions, and constraints. Minimizing the total risk yields an optimal dosing strategy, estimated as dose sizes for different subpopulations and covariate cutoff values at which doses are increased or decreased. The method was illustrated with the use of simulated and real drug examples for the situation in which clearance is related to creatinine clearance. RESULTS: The estimated optimal cutoff(s) paralleled the median creatinine clearance in the population. The extent of variability in clearance explained by creatinine clearance was the main factor influencing the optimal ratios between adjacent dose sizes. An optimal dosing strategy was possible to estimate for the real drug. CONCLUSIONS: The method is simple to perform, although one difficulty lies in defining the target variable and risk function. Our results imply that commonly used constraints in dosing strategies based on renal function (ie, dose ratio of 2 and predetermined cutoffs) are nonoptimal in the sense we propose. Because an optimal dosing strategy may not be practical to use, the therapeutic cost that would result with any constraint can be assessed by comparison of the outcome after the desired and the optimal strategy.

  • 78.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Estimation of dosing strategies aiming at maximizing utility or responder probability, using oxybutynin as an example drug2005In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, no 1, p. 123-132Article in journal (Refereed)
    Abstract [en]

    Methods for optimizing dosing strategies for individualization with a limited number of discrete doses, in terms of maximizing the expected utility of treatment or responder probability, are presented. The optimality criteria require models for both beneficial and adverse effects that are part of the utility definition and published population models describing those effects for oxybutynin (urge urinary incontinence episodes per week and severity of dry mouth, respectively) were used for illustration. Dosing strategies with two dosing categories were defined in terms of sizes of the daily doses (low and high dose) and the proportion of patients that can be expected to be preferentially treated at the low dose level. Utility and responder definitions were varied to investigate the influence on the resulting dosing strategy. By minimizing a risk function, describing the seriousness of deviations from the predefined target, optimal dosing strategies were estimated using mixture models in NONMEM. The estimated dose ranges for oxybutynin were similar to those recommended. The optimal individualization conditions were dependent on the definitions of responder and utility. The predicted gain of individualization given utility and responder definitions used was greater, when a responder criteria was maximized compared with maximizing utility.

  • 79.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Estimating bias in population parameters for some models for repeated measures ordinal data using NONMEM or NLMIXED2004In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 31, no 4, p. 299-320Article in journal (Refereed)
    Abstract [en]

    The application of proportional odds models to ordered categorical data using the mixed-effects modeling approach has become more frequently reported within the pharmacokinetic/pharmacodynamic area during the last decade. The aim of this paper was to investigate the bias in parameter estimates, when models for ordered categorical data were estimated using methods employing different approximations of the likelihood integral; the Laplacian approximation in NONMEM (without and with the centering option) and NLMIXED, and the Gaussian quadrature approximations in NLMIXED. In particular, we have focused on situations with non-even distributions of the response categories and the impact of interpatient variability. This is a Monte Carlo simulation study where original data sets were derived from a known model and fixed study design. The simulated response was a four-category variable on the ordinal scale with categories 0, 1, 2 and 3. The model used for simulation was fitted to each data set for assessment of bias. Also, simulations of new data based on estimated population parameters were performed to evaluate the usefulness of the estimated model. For the conditions tested, Gaussian quadrature performed without appreciable bias in parameter estimates. However, markedly biased parameter estimates were obtained using the Laplacian estimation method without the centering option, in particular when distributions of observations between response categories were skewed and when the interpatient variability was moderate to large. Simulations under the model could not mimic the original data when bias was present, but resulted in overestimation of rare events. The bias was considerably reduced when the centering option in NONMEM was used. The cause for the biased estimates appears to be related to the conditioning on uninformative and uncertain empirical Bayes estimate of interindividual random effects during the estimation, in conjunction with the normality assumption.

  • 80.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Matolcsi, Katalin
    Mentré, France
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Factors influencing the choice of optimal individualized dosing strategies targeting a drug concentration or effect2004In: AAPS PharmSci, ISSN 1522-1059Article in journal (Refereed)
  • 81.
    Kausland, Maren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Utvärdering av Utskrivningshjälpen- en farmaceutisk tjänst för slutenvårdspatienter som skrivs ut till Uppsala läns korttidsboenden2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Läkemedelsfel uppstår ofta i övergångar då patienter skrivs ut från en vårdande enhet till en annan. Utskrivningshjälpen startades då flera avvikelser gällande patienter som skrevs ut till korttidsboenden hade uppmärksammats. Syfte: Utvärdera Utskrivningshjälpen för att uppskatta eventuella kvalitets- och säkerhetsvinster i läkemedelsanvändning och bedöma upplevd nytta med tjänsten. Material och metoder: Studien innefattade granskning av journaldata för att sammanställa diskrepanser farmaceuterna identifierade, samt att kartlägga de arbetsuppgifter som utfördes inför varje utskrivning. Det genomfördes också en enkätundersökning riktad till sjuk-sköterskor på vårdavdelningar och korttidsboenden för att belysa eventuella kvalitets- och säkerhetsvinster för läkemedelsanvändningen samt deras uppskattningar om en eventuell tidsbesparning. Resultat: 243 patienter skrevs ut under studieperioden. Hos totalt 127 patienter identifierades 422 diskrepanser. 228 av de identifierade diskrepanserna gällde behov av läkemedelsutsättning, 36 gällde insättning och 58 gällde behov av dosjustering i läkemedelslista. 62 sjuksköterskor svarade på enkäten och ungefär 80 % uppskattade att Utskrivningshjälpen medförde kvalitet- och säkerhetsvinster inom läkemedelsanvändningen. Medelvärdet för uppskattad tidsbesparing var 42 minuter per patient. Konklusion: Utskrivningshjälpen bidrar till mer korrekta läkemedelslistor inför utskrivning vilket i sin tur ökar patientsäkerheten. Tjänsten underlättar även för övrig vårdpersonal och bidrar till ökad trygghet vid läkemedelfrågor och hantering.

  • 82.
    Kerbusch, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wählby, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Milligan, Peter A
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability2003In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 56, no 6, p. 639-652Article in journal (Refereed)
    Abstract [en]

    AIMS: A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies. The relationships between explanatory covariates and pharmacokinetic parameters were explored. METHODS: Plasma concentration data from 337 individuals were pooled from 17 Phase 1 studies (median 28/33 darifenacin/metabolite observations per healthy subject), and one Phase 2 study (median 7/7 darifenacin/metabolite observations per subject) encompassing one intravenous and five different oral formulations (1-45 mg). RESULTS: Non-linear Mixed Effects Models (NONMEM Version VI) described both the population pharmacokinetics of darifenacin and its hydroxylated metabolite with a two-compartment disposition model with first order absorption. The values (mean +/- standard error of the mean) for clearance (CL) and volume of distribution of the central compartment were 40.2 +/- 2.0 l h-1 and 34.7 +/- 4.6 l h-1, respectively, in a typical male CYP2D6 homozygote-extensive metabolizer (Hom-EM). The absolute bioavailability (F) of darifenacin in a Hom-EM after doses of 7.5, 15 or 30 mg extended release formulation (CR) was 15, 19 and 25%, respectively. Factors influencing F were formulation (70-110% higher for CR compared with immediate release following equivalent daily doses), CYP2D6 genotype [heterozygote-extensive metabolizers (Het-EM) and poor metabolizers (PM) experienced 40 and 90%, respectively, higher exposure than Hom-EM irrespective of dose administered] and saturable first-pass metabolism (dose nonlinearity 1.05-1.43-fold). Race affected F, which was 56% lower in Japanese males. The CYP3A4 inhibitors ketoconazole and erythromycin increased F to approximately 100% and ketoconazole decreased CL by 67.5%. CL was 31% lower in females and 10% lower at night. Formulation affected the metabolite absorption/formation rate. Ketoconazole and erythromycin administration resulted in a decrease of 61.2 and 28.8% in exposure to the metabolite, respectively. The covariates race, gender and circadian rhythm accounted for only approximately half of the variability in the estimated exposures to darifenacin. CONCLUSIONS: The pooled analysis provided a descriptive integration of all characteristics and covariates of the pharmacokinetics of darifenacin and its metabolite, enabling interpolation and extrapolation of these key factors.

  • 83.
    Khadra, Cham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Vilka datorbaserade doseringsverktyg finns för meropenem och piperacillin och hur skiljer de sig åt?2019Independent thesis Advanced level (degree of Master (One Year)), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakgrund: IVA-patienter vårdas på intensivvårdsavdelningar av specialutbildad hälsooch sjukvårdspersonal med mål att ge maximal möjlighet till överlevnad. Sepsis är ett vanligt förekommande tillstånd hos IVA-patienter som medför svikt i vitala organ och ökad mortalitet. Denna patientgrupp uppvisar distinkta variationer i farmakokinetiska aspekter vilket resulterar i att de oftast underbehandlas eftersom dosregim i svensk vård inte är anpassad efter de variationer som kan uppstå. Bayesiansk TDM är ett datorbaserat doseringsverktyg som ger doseringsförslag med hänsyn tagen till patientens individvärden. Syfte: Att kartlägga dem tillgängliga datorbaserade doseringsverktygen för meropenem och/eller piperacillin och jämföra resultat från de utvalda doseringsverktygen avseende kinetikparameterar och doseringsförslag utifrån patientdata för meropenem. Metod: En översiktsartikel och presentation gällande de befintliga datorbaserade doseringsverktygen användes som startpunkt för identifieringen. Återstående doseringsverktyg identifierades genom en litteratursökning. Information beträffande karaktär, funktioner och farmakokinetiska aspekter för kartläggningen insamlades via den information som fanns att tillgå. Kriterier för doseringsförslag identifierades och patientdata för meropenem användes för att ta fram resultat gällande beräknade kinetikparametrar och rekommenderat dosregim. Resultat: Fem stycken datorbaserade doseringsverktyg inkluderades i kartläggningen varav resultatet visade att det framkom skillnader beträffande deras funktioner och farmakokinetiska aspekter. Resultaten visade att DoseMe gav relativt lägre värden på beräknade meropenem CL i jämförelse med demandra doseringsverktygen och TDMx var det enda doseringsverktyget som fångade upp extremvärden. Beträffande de föreslagna doseringsregimerna visade resultaten att de beräknade a posterioridoserna varierade från de givna standardosering. Slutsats: Det uppkom skillnader i utfallen från dessa doseringsverktyg och för att välja ett idealt bayesiansk TDM-verktyg behöver de ha en relevant patientmodell och dosregim som kan tillämpas i svensk vård.

  • 84.
    Khessib, Jasmin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Rationale for dose-drug combinations in pulmonary tuberculosis2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium Tuberculosis. The first-line regimen consists of rifampicin (RMP), isoniazid (INH), ethambutol (EMB) and pyrazinamide (PZA) daily for two months followed by RMP and INH daily for additional four months, with doses depending on patient’s body weight. Current dose rationale does not have scientific basis and was developed based on empiric observations. It is unclear whether the drug combinations and such long treatment are required to obtain relapse-free cure. The aim of this project was to demonstrate how pharmacokinetic-pharmacodynamic (PKPD) relationships can be used to evaluate if different doses of the standard care drugs could reduce the treatment time and to find suitable drug combinations, by examine the effect on drug efficacy by adding INH, PZA and EMB to RMP.  The early bactericidal activity during the first 14 days (EBA0-14) following treatment was characterised using a model based approach in conjunction with preclinical PKPD data. PKPD modeling and simulation was performed using a non-linear mixed effect approach as implemented in NONMEM 7.3. Data manipulation and graphical visualisation was performed in R v.3.3.1. The results showed that the in-vivo PKPD RMP mouse model could predict human EBA0-14. A model developed on clinical EBA0-14 data was subsequently able to predict culture conversion after two months of treatment. Findings suggested that the treatment could be reduced from six to four months with increased dose of RMP. Some patients might be underdosed with the current dosing regimen. The role of EMB in present first-line combination therapy can be questioned. Further studies are warranted to provide more robust and accurate information on choosing the optimal drug combination and dosing regimen.

  • 85.
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Methodological Studies on Models and Methods for Mixed-Effects Categorical Data Analysis2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Effects of drugs are in clinical trials often measured on categorical scales. These measurements are increasingly being analyzed using mixed-effects logistic regression. However, the experience with such analyzes is limited and only a few models are used.

    The aim of this thesis was to investigate the performance and improve the use of models and methods for mixed-effects categorical data analysis. The Laplacian method was shown to produce biased parameter estimates if (i) the data variability is large or (ii) the distribution of the responses is skewed. Two solutions are suggested; the Gaussian quadrature method and the back-step method. Two assumptions made with the proportional odds model have also been investigated. The assumption with proportional odds for all categories was shown to be unsuitable for analysis of data arising from a ranking scale of effects with several underlying causes. An alternative model, the differential odds model, was developed and shown to be an improvement, in regard to statistical significance as well as predictive performance, over the proportional odds model for such data. The appropriateness of the likelihood ratio test was investigated for an analysis where dependence between observations is ignored, i.e. performing the analysis using the proportional odds model. The type I error was found to be affected; thus assessing the actual critical value is prudent in order to verify the statistical significance level. An alternative approach is to use a Markov model, in which dependence between observations is incorporated. In the case of polychotomous data such model may involve considerable complexity and thus, a strategy for the reduction of the time-consuming model building with the Markov model and sleep data is presented.

    This thesis will hopefully contribute to a more confident use of models for categorical data analysis within the area of pharmacokinetic and pharmacodynamic modelling in the future.

    List of papers
    1. Estimating bias in population parameters for some models for repeated measures ordinal data using NONMEM or NLMIXED
    Open this publication in new window or tab >>Estimating bias in population parameters for some models for repeated measures ordinal data using NONMEM or NLMIXED
    2004 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 31, no 4, p. 299-320Article in journal (Refereed) Published
    Abstract [en]

    The application of proportional odds models to ordered categorical data using the mixed-effects modeling approach has become more frequently reported within the pharmacokinetic/pharmacodynamic area during the last decade. The aim of this paper was to investigate the bias in parameter estimates, when models for ordered categorical data were estimated using methods employing different approximations of the likelihood integral; the Laplacian approximation in NONMEM (without and with the centering option) and NLMIXED, and the Gaussian quadrature approximations in NLMIXED. In particular, we have focused on situations with non-even distributions of the response categories and the impact of interpatient variability. This is a Monte Carlo simulation study where original data sets were derived from a known model and fixed study design. The simulated response was a four-category variable on the ordinal scale with categories 0, 1, 2 and 3. The model used for simulation was fitted to each data set for assessment of bias. Also, simulations of new data based on estimated population parameters were performed to evaluate the usefulness of the estimated model. For the conditions tested, Gaussian quadrature performed without appreciable bias in parameter estimates. However, markedly biased parameter estimates were obtained using the Laplacian estimation method without the centering option, in particular when distributions of observations between response categories were skewed and when the interpatient variability was moderate to large. Simulations under the model could not mimic the original data when bias was present, but resulted in overestimation of rare events. The bias was considerably reduced when the centering option in NONMEM was used. The cause for the biased estimates appears to be related to the conditioning on uninformative and uncertain empirical Bayes estimate of interindividual random effects during the estimation, in conjunction with the normality assumption.

    Keywords
    NONMEM, NLMIXED, SAS, Laplacian, Gaussian quadrature, maximum likelihood estimation, ordered categorical, proportional odds model, bias in parameter estimates
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91736 (URN)10.1023/B:JOPA.0000042738.06821.61 (DOI)15563005 (PubMedID)
    Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2017-12-14
    2. The back-step method: method for obtaining unbiased population parameter estimates for ordered categorical data
    Open this publication in new window or tab >>The back-step method: method for obtaining unbiased population parameter estimates for ordered categorical data
    2004 (English)In: AAPS Journal, E-ISSN 1550-7416, Vol. 6, no 3, p. 13-22Article in journal (Refereed) Published
    Abstract [en]

    A significant bias in parameters, estimated with the proportional odds model using the software NONMEM, has been reported. Typically, this bias occurs with ordered categorical data, when most of the observations are found at one extreme of the possible outcomes. The aim of this study was to assess, through simulations, the performance of the Back-Step Method (BSM), a novel approach for obtaining unbiased estimates when the standard approach provides biased estimates. BSM is an iterative method involving sequential simulation-estimation steps. BSM was compared with the standard approach in the analysis of a 4-category ordered variable using the Laplacian method in NONMEM. The bias in parameter estimates and the accuracy of model predictions were determined for the 2 methods on 3 conditions: (1) a nonskewed distribution of the response with low interindividual variability (IIV), (2) a skewed distribution with low IIV, and (3) a skewed distribution with high IIV. An increase in bias with increasing skewness and IIV was shown in parameters estimated using the standard approach in NONMEM. BSM performed without appreciable bias in the estimates under the 3 conditions, and the model predictions were in good agreement with the original data. Each BSM estimation represents a random sample of the population; hence, repeating the BSM estimation reduces the imprecision of the parameter estimates. The BSM is an accurate estimation method when the standard modeling approach in NONMEM gives biased estimates.

    Keywords
    ordered categorical, proportional odds model, bias in parameter estimates, NONMEM, Laplacian, pharmacodynamics
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97669 (URN)10.1208/aapsj060319 (DOI)15760104 (PubMedID)
    Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2023-08-28
    3. Comparison of proportional odds and differential odds models for mixed-effects analysis of categorical data
    Open this publication in new window or tab >>Comparison of proportional odds and differential odds models for mixed-effects analysis of categorical data
    2008 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, no 5, p. 483-501Article in journal (Refereed) Published
    Abstract [en]

    In this work a model for analyzing categorical data is presented; the differential odds model. Unlike the commonly used proportional odds model, this model does not assume that a covariate affects all categories equally on the log odds scale. The differential odds model was compared to the proportional odds model, by assessing statistical significance and improvement of predictive performance when applying the differential odds model to data previously analyzed using the proportional odds model. Three clinical studies; 3-category T-cell receptor density data, 5-category diarrhea data and 6-category sedation data, were re-analyzed with the differential odds model. As expected, no improvements were seen with T-cell receptor density and diarrhea data. However, for the more complex measurement sedation, the differential odds model provided both statistical improvements and improvements in simulation properties. The estimated actual critical value was for all data lower than the nominal value, using the number of added parameters as the degree of freedom, i.e. the differential odds model is statistically indicated to a less extent than expected. The differential odds model had the desired property of not being indicated when not necessary, but it may provide improvements when the data does not represent a categorization of continuous data.

    Keywords
    NONMEM, Mixed-effects models, Pharmacodynamics, Categorical data, Proportional odds model, Differential odds model
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97670 (URN)10.1007/s10928-008-9098-0 (DOI)000262699200001 ()
    Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2017-12-14
    4. The impact of misspecification of residual error or correlation structure on the type I error rate for covariate inclusion
    Open this publication in new window or tab >>The impact of misspecification of residual error or correlation structure on the type I error rate for covariate inclusion
    2009 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 36, no 1, p. 81-99Article in journal (Refereed) Published
    Abstract [en]

    It has been shown that when using the FOCE method in NONMEM, the likelihood ratio test (LRT) can be sensitive to the use of an inappropriate estimation method in that ignoring an existing eta-epsilon interaction leads to actual significance levels for type I errors being higher than the nominal levels. The objective of this study was to assess through simulations the LRT sensitivity to various types of residual error model misspecifications in both continuous and categorical data. The study contained two parts, simulations based on continuous and categorical data. Data sets containing 250 individuals with up to 24 observations per individual were simulated multiple times (1000) with different types of residual error models for the continuous data and different strength of correlation between observations for the categorical data. The data sets were analyzed using either the correct or a simpler (incorrect) model with or without addition of a covariate. The type I error rate of inclusion of the non-informative covariate on the 5% level was calculated as the number of runs where the drop in the objective function value (OFV) was larger than 3.84 when the covariate relationship was included in the model using the correct or the incorrect model. The difference in OFV between the model with the correct and the incorrect structure was also calculated as a measure of the residual error model misspecification. For continuous data the FOCE method was used in most cases (with interaction when appropriate). The Laplacian estimation method was used for one of the continuous models and for categorical data. The results showed that the residual error model misspecifications when the erroneous model was used were pronounced, as indicated by the OFV being substantially higher than for the corresponding correct models. The significance levels of the LRT with the incorrect model were appropriate in all cases but ignoring (serial) correlations between observations (continuous and categorical data) as well as when the eta-epsilon interaction was ignored (which has previously been shown, continuous data). When ignoring correlation, the type I error rates were shown to be sensitive to the correlation strength, the number of observations per individual and the magnitude of the inter-individual variability on clearance. We conclude that the LRT appears robust towards all tested cases, but ignoring (serial) correlations between observations and eta-epsilon interaction.

    Keywords
    Residual error, Model misspecification, Continuous data, Categorical data, NONMEM, Markov model, Proportional odds model, Simulation, Likelihood ratio test
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-99064 (URN)10.1007/s10928-009-9112-1 (DOI)000263797800005 ()19219538 (PubMedID)
    Available from: 2009-03-09 Created: 2009-03-06 Last updated: 2022-01-28
    5. Modeling sleep data for a new drug in development using Markov mixed-effects models
    Open this publication in new window or tab >>Modeling sleep data for a new drug in development using Markov mixed-effects models
    2011 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 28, no 10, p. 2610-2627Article in journal (Refereed) Published
    Abstract [en]

    To characterize the time-course of sleep in insomnia patients as well as placebo and concentration-effect relationships of two hypnotic compounds, PD 0200390 and zolpidem, using an accelerated model-building strategy based on mixed-effects Markov models. Data were obtained in a phase II study with the drugs. Sleep stages were recorded during eight hours of sleep for two nights per treatment for the five treatments. First-order Markov models were developed for one transition at a time in a sequential manner; first a baseline model, followed by placebo and lastly the drug models. To accelerate the process, predefined models were selected based on a priori knowledge of sleep, including inter-subject and inter-occasion variability. Baseline sleep was described using piece-wise linear models, depending on time of night and duration of sleep stage. Placebo affected light sleep stages; drugs also affected slow-wave sleep. Administering PD 0200390 30 min earlier than standard dosing was shown through simulations to reduce latency to persistent sleep by 40%. The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments.

    Keywords
    Markov model, NONMEM, pharmacodynamics, polysomnography, population analysis, sleep, transition model, zolpidem
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97672 (URN)10.1007/s11095-011-0490-x (DOI)000294811700023 ()
    Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2017-12-14Bibliographically approved
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  • 86.
    Kjellsson, Maria C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    The back-step method: method for obtaining unbiased population parameter estimates for ordered categorical data2004In: AAPS Journal, E-ISSN 1550-7416, Vol. 6, no 3, p. 13-22Article in journal (Refereed)
    Abstract [en]

    A significant bias in parameters, estimated with the proportional odds model using the software NONMEM, has been reported. Typically, this bias occurs with ordered categorical data, when most of the observations are found at one extreme of the possible outcomes. The aim of this study was to assess, through simulations, the performance of the Back-Step Method (BSM), a novel approach for obtaining unbiased estimates when the standard approach provides biased estimates. BSM is an iterative method involving sequential simulation-estimation steps. BSM was compared with the standard approach in the analysis of a 4-category ordered variable using the Laplacian method in NONMEM. The bias in parameter estimates and the accuracy of model predictions were determined for the 2 methods on 3 conditions: (1) a nonskewed distribution of the response with low interindividual variability (IIV), (2) a skewed distribution with low IIV, and (3) a skewed distribution with high IIV. An increase in bias with increasing skewness and IIV was shown in parameters estimated using the standard approach in NONMEM. BSM performed without appreciable bias in the estimates under the 3 conditions, and the model predictions were in good agreement with the original data. Each BSM estimation represents a random sample of the population; hence, repeating the BSM estimation reduces the imprecision of the parameter estimates. The BSM is an accurate estimation method when the standard modeling approach in NONMEM gives biased estimates.

  • 87.
    Kjellsson, Maria C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ouellet, Daniele
    Corrigan, Brian
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Modeling sleep data for a new drug in development using Markov mixed-effects models2011In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 28, no 10, p. 2610-2627Article in journal (Refereed)
    Abstract [en]

    To characterize the time-course of sleep in insomnia patients as well as placebo and concentration-effect relationships of two hypnotic compounds, PD 0200390 and zolpidem, using an accelerated model-building strategy based on mixed-effects Markov models. Data were obtained in a phase II study with the drugs. Sleep stages were recorded during eight hours of sleep for two nights per treatment for the five treatments. First-order Markov models were developed for one transition at a time in a sequential manner; first a baseline model, followed by placebo and lastly the drug models. To accelerate the process, predefined models were selected based on a priori knowledge of sleep, including inter-subject and inter-occasion variability. Baseline sleep was described using piece-wise linear models, depending on time of night and duration of sleep stage. Placebo affected light sleep stages; drugs also affected slow-wave sleep. Administering PD 0200390 30 min earlier than standard dosing was shown through simulations to reduce latency to persistent sleep by 40%. The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments.

  • 88.
    Kjellsson, Maria C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Zingmark, Per-Henrik
    Jonsson, E. Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Comparison of proportional odds and differential odds models for mixed-effects analysis of categorical data2008In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, no 5, p. 483-501Article in journal (Refereed)
    Abstract [en]

    In this work a model for analyzing categorical data is presented; the differential odds model. Unlike the commonly used proportional odds model, this model does not assume that a covariate affects all categories equally on the log odds scale. The differential odds model was compared to the proportional odds model, by assessing statistical significance and improvement of predictive performance when applying the differential odds model to data previously analyzed using the proportional odds model. Three clinical studies; 3-category T-cell receptor density data, 5-category diarrhea data and 6-category sedation data, were re-analyzed with the differential odds model. As expected, no improvements were seen with T-cell receptor density and diarrhea data. However, for the more complex measurement sedation, the differential odds model provided both statistical improvements and improvements in simulation properties. The estimated actual critical value was for all data lower than the nominal value, using the number of added parameters as the degree of freedom, i.e. the differential odds model is statistically indicated to a less extent than expected. The differential odds model had the desired property of not being indicated when not necessary, but it may provide improvements when the data does not represent a categorization of continuous data.

  • 89. Kloft, Charlotte
    et al.
    Wallin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Henningsson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Chatelut, Etienne
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs2006In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 12, no 18, p. 5481-5490Article in journal (Refereed)
    Abstract [en]

    Purpose: Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs.

    Experimental Design: Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made.

    Results: A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and alpha(1)-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction.

    Conclusions: These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use.

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  • 90. Kruse, Anja
    et al.
    Uehlinger, Dominik E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Gotch, Frank
    Kotanko, Peter
    Levin, Nathan W.
    Red blood cell lifespan, erythropoiesis and hemoglobin control.2008In: Contributions to Nephrology, ISSN 0302-5144, E-ISSN 1662-2782, Vol. 161, p. 247-254Article in journal (Refereed)
    Abstract [en]

    Erythropoietin (EPO) and iron deficiency as causes of anemia in patients with limited renal function or end-stage renal disease are well addressed. The concomitant impairment of red blood cell (RBC) survival has been largely neglected. Properties of the uremic environment like inflammation, increased oxidative stress and uremic toxins seem to be responsible for the premature changes in RBC membrane and cytoskeleton. The exposure of antigenic sites and breakdown of the phosphatidylserine asymmetry promote RBC phagocytosis. While the individual response to treatment with EPO-stimulating agents (ESA) depends on both the RBC's lifespan and the production rate, uniform dosing algorithms do not meet that demand. The clinical use of mathematical models predicting ESA-induced changes in hematocrit might be greatly improved once independent estimates of RBC production rate and/or lifespan become available, thus making the concomitant estimation of both parameters unnecessary. Since heme breakdown by the hemoxygenase pathway results in carbon monoxide (CO) which is exhaled, a simple CO breath test has been used to calculate hemoglobin turnover and therefore RBC survival and lifespan. Future research will have to be done to validate and implement this method in patients with kidney failure. This will result in new insights into RBC kinetics in renal patients. Eventually, these findings are expected to improve our understanding of the hemoglobin variability in response to ESA.

  • 91.
    König, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Distribution of unbound D2-antagonists in rat frontal cortex, striatum and corpus callosum; a pilot study2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Introduction: To estimate the distribution of a drug in brain tissue, the unbound volume of distribution (Vu,brain) using the in vitro brain slice technique was employed. Previously, Vu,brain has only been calculated for the entire brain, and no consideration has been given to the different regions. Since the regions of the brain have different gene- and protein expression and neural cell representation, it is reasonable to presume that drugs entering the brain will have different distribution pattern in different regions. This may potentially affect the fraction of unbound drug in the distinct brain region and consequently the extent of pharmacological response of neuroleptics.

    Aim: The aim with the study was to increase the knowledge about region specific distribution and binding of drugs through investigation Vu,brain of paliperidone, clozapine, olanzapine and quetiapine, in the cortex, striatum and corpus callosum of the rat using the brain slice method.

    Materials and Methods: The study was conducted through the brain slice method. Six 300µm brain slices were incubated for five hours in a buffer containing the compounds (200 nM). At the end of the incubation, the buffer and brain slice samples were taken to analyse the concentration of compounds. The brain slices were either analysed as a whole or after micro-dissection to separate areas of frontal cortex, striatum and corpus callosum. The ratio between the amount of the drug in the brain slice and concentration in buffer was used to calculate Vu,brain.

    Results: Vu,brain of all compounds were significantly higher in striatum compared to the whole brain, and Vu,brain in cortex was slightly elevated. There were no differences in Vu,brain of the studied drugs estimated using cassette and individual compound incubation approaches.

    Conclusions:  This is the first effort to microdissect specific regions from the slice to calculate Vu,brain in different regions. The results show that there is a region-specific distribution of D2-antagonist, and this opens up opportunities for further studies and experiments.

  • 92.
    Langdon, Grant
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Gueorguieva, Ivelina
    Aarons, Leon
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Linking preclinical and clinical whole-body physiologically based pharmacokinetic models with prior distributions in NONMEM2007In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, no 5, p. 485-498Article in journal (Refereed)
    Abstract [en]

    Purpose: The aim of this study was to evaluate the performance of the NONMEM prior functionality compared to a full Bayesian method when applied to population physiological models using diazepam as a case study. Methods: Whole-body physiologically based pharmacokinetic (WBPBPK) models for diazepam were initially developed, tested and calibrated for rats and man using a full Bayesian analysis as implemented in WinBUGS. The final models were implemented in NONMEM and the results from the two analyses compared in terms of parameter estimates, measures of parameter precision and run times. Results: NONMEM population parameter estimates were in close agreement with those produced by the Bayesian analysis although there was a substantial shortening of run time for both the animal WBPBPK model (4.5 vs. 21 h) and human WBPBPK models (2 vs. 167 h). The adequacy of the model and the final parameter estimates were judged to be sufficient by the model's ability to describe individual tissue concentration-time profiles. The model provided a good overall description of the plasma concentration-time data in both rat and man with comparable parameter precision. A limited nonparametric bootstrap (n = 50) was performed to assess parameter sensitivity, bias and imprecision. No systematic bias was seen when comparing bootstrap means to final parameter estimates. Conclusions: The ease of implementation and reductions in run time hopefully provide a further step forward in allowing the wider use of these complex and information-rich models together with clinical data in the future.

  • 93. Langdon, Grant
    et al.
    Wilkins, Justin
    McFadyen, Lynn
    McIlleron, Helen
    Smith, Peter
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Population pharmacokinetics of rifapentine and its primary desacetyl metabolite in South African tuberculosis patients2005In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 49, no 11, p. 4429-4436Article in journal (Refereed)
    Abstract [en]

    This study was designed to describe the population pharmacokinetics of rifapentine (RFP) and 25-desacetyl RFP in a South African pulmonary tuberculosis patient population. Special reference was made to studying the influence of previous exposure to rifampin (RIF) and the variability in pharmacokinetic parameters between patients and between occasions and the influence of different covariates. Patients were included in the study if they had been receiving first-line antimycobacterial therapy (rifampin, isoniazid, pyrazinamide, and ethambutol) for not less than 4 weeks and not more than 6 weeks and were divided into three RFP dosage groups based on weight: 600 mg, <45 kg; 750 mg, 46 to 55 kg; and 900 mg, >55 kg. Participants received a single oral dose of RFP together with concomitant antimycobacterial agents, excluding RIF, on study days 1 and 5 after they ingested a soup-based meal. The RFP and 25-desacetyl RFP concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM. The pharmacokinetics of the parent drug were modeled separately, and the individual pharmacokinetic parameters were used as inputs for the 25-desacetyl RFP pharmacokinetic model. A one-compartment disposition model was found to best describe the data for both the parent and the metabolite, and the metabolite was assumed to be formed only from the central compartment of the parent drug. Prior treatment with RIF did not alter the pharmacokinetics of RFP but appeared to increase the excretion of 25-desacetyl RFP in a nonlinear fashion. The RFP oral clearance and volume of distribution were found to increase by 0.049 liter/h and 0.691 liter, respectively, with a 1-kg increase from the median weight of 50 kg. The oral clearance of 25-desacetyl RFP was found to be 35% lower in female patients. The model developed here describes the population pharmacokinetics of RFP and its primary metabolite in tuberculosis patients and includes the effects of prior administration with RIF and covariate factors.

  • 94.
    Lindbom, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Development, Application and Evaluation of Statistical Tools in Pharmacometric Data Analysis2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pharmacometrics uses models based on pharmacology, physiology and disease for quantitative analysis of interactions between drugs and patients. The availability of software implementing modern statistical methods is important for efficient model building and evaluation throughout pharmacometric data analyses.

    The aim of this thesis was to facilitate the practical use of available and new statistical methods in the area of pharmacometric data analysis. This involved the development of suitable software tools that allows for efficient use of these methods, characterisation of basic properties and demonstration of their usefulness when applied to real world data. The thesis describes the implementation of a set of statistical methods (the bootstrap, jackknife, case-deletion diagnostics, log-likelihood profiling and stepwise covariate model building), made available as tools through the software Perl-speaks-NONMEM (PsN). The appropriateness of the methods and the consistency of the software tools were evaluated using a large selection of clinical and nonclinical data. Criteria based on clinical relevance were found to be useful components in automated stepwise covariate model building. Their ability to restrict the number of included parameter-covariate relationships while maintaining the predictive performance of the model was demonstrated using the antiarrythmic drug dofetilide. Log-likelihood profiling was shown to be equivalent to the bootstrap for calculating confidence intervals for fixed-effects parameters if an appropriate estimation method is used. The condition number of the covariance matrix for the parameter estimates was shown to be a good indicator of how well resampling methods behave when applied to pharmacometric data analyses using NONMEM. The software developed in this thesis equips modellers with an enhanced set of tools for efficient pharmacometric data analysis.

    List of papers
    1. Perl-speaks-NONMEM (PsN) – a Perl module for NONMEM related programming
    Open this publication in new window or tab >>Perl-speaks-NONMEM (PsN) – a Perl module for NONMEM related programming
    2004 (English)In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 75, no 2, p. 85-94Article in journal (Refereed) Published
    Abstract [en]

    The NONMEM program is the most widely used nonlinear regression software in population pharmacokinetic/pharmacodynamic (PK/PD) analyses. In this article we describe a programming library, Perl-speaks-NONMEM (PsN), intended for programmers that aim at using the computational capability of NONMEM in external applications. The library is object oriented and written in the programming language Perl. The classes of the library are built around NONMEM's data, model and output files. The specification of the NONMEM model is easily set or changed through the model and data file classes while the output from a model fit is accessed through the output file class. The classes have methods that help the programmer perform common repetitive tasks, e.g. summarising the output from a NONMEM run, setting the initial estimates of a model based on a previous run or truncating values over a certain threshold in the data file. PsN creates a basis for the development of high-level software using NONMEM as the regression tool.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94377 (URN)10.1016/j.cmpb.2003.11.003 (DOI)15212851 (PubMedID)
    Available from: 2006-04-21 Created: 2006-04-21 Last updated: 2017-12-14Bibliographically approved
    2. PsN-Toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM
    Open this publication in new window or tab >>PsN-Toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM
    2005 In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, Vol. 79, no 3, p. 17-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94378 (URN)
    Available from: 2006-04-21 Created: 2006-04-21Bibliographically approved
    3. The use of clinical irrelevance criteria in covariate model building with application to dofetilide pharmacokinetic data
    Open this publication in new window or tab >>The use of clinical irrelevance criteria in covariate model building with application to dofetilide pharmacokinetic data
    Show others...
    2008 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, no 5, p. 503-526Article in journal (Refereed) Published
    Abstract [en]

    To characterise the pharmacokinetics of dofetilide in patients and to identify clinically relevant parameter-covariate relationships. To investigate three different modelling strategies in covariate model building using dofetilide as an example: (1) using statistical criteria only or in combination with clinical irrelevance criteria for covariate selection, (2) applying covariate effects on total clearance or separately on non-renal and renal clearances and (3) using separate data sets for covariate selection and parameter estimation. Pooled concentration-time data (1,445 patients, 10,133 observations) from phase III clinical trials was used. A population pharmacokinetic model was developed using NONMEM. Stepwise covariate model building was applied to identify important covariates using the strategies described above. Inclusion and exclusion of covariates using clinical irrelevance was based on reduction in interindividual variability and changes in parameters at the extremes of the covariate distribution. Parametric separation of the elimination pathways was accomplished using creatinine clearance as an indicator of renal function. The pooled data was split in three parts which were used for covariate selection, parameter estimation and evaluation of predictive performance. Parameter estimations were done using the first-order (FO) and the first-order conditional estimation (FOCE) methods. A one-compartment model with first order absorption adequately described the data. Using clinical irrelevance criteria resulted in models containing less parameter-covariate relationships with a minor loss in predictive power. A larger number of covariates were found significant when the elimination was divided into a renal part and a non-renal part, but no gain in predictive power could be seen with this data set. The FO and FOCE estimation methods gave almost identical final covariate model structures with similar predictive performance. Clinical irrelevance criteria may be valuable for practical reasons since stricter inclusion/exclusion criteria shortens the run times of the covariate model building procedure and because only the covariates important for the predictive performance are included in the model.

    Keywords
    Covariates, Dofetilide, Modelling, NONMEM
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94379 (URN)10.1007/s10928-008-9099-z (DOI)000262699200002 ()19011957 (PubMedID)
    Available from: 2006-04-21 Created: 2006-04-21 Last updated: 2022-01-28Bibliographically approved
    4. Evaluating the evaluations: resampling methods for determining model appropriateness in pharmacometric data analysis
    Open this publication in new window or tab >>Evaluating the evaluations: resampling methods for determining model appropriateness in pharmacometric data analysis
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94380 (URN)
    Available from: 2006-04-21 Created: 2006-04-21 Last updated: 2011-03-01
    Download full text (pdf)
    FULLTEXT01
    Download (pdf)
    COVER01
  • 95.
    Lindbom, Lars
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Pihlgren, Pontus
    Jonsson, E Niclas
    PsN-Toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM2005In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, Vol. 79, no 3, p. 17-Article in journal (Refereed)
  • 96.
    Lindbom, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ribbing, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jonsson, E Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Perl-speaks-NONMEM (PsN) – a Perl module for NONMEM related programming2004In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 75, no 2, p. 85-94Article in journal (Refereed)
    Abstract [en]

    The NONMEM program is the most widely used nonlinear regression software in population pharmacokinetic/pharmacodynamic (PK/PD) analyses. In this article we describe a programming library, Perl-speaks-NONMEM (PsN), intended for programmers that aim at using the computational capability of NONMEM in external applications. The library is object oriented and written in the programming language Perl. The classes of the library are built around NONMEM's data, model and output files. The specification of the NONMEM model is easily set or changed through the model and data file classes while the output from a model fit is accessed through the output file class. The classes have methods that help the programmer perform common repetitive tasks, e.g. summarising the output from a NONMEM run, setting the initial estimates of a model based on a previous run or truncating values over a certain threshold in the data file. PsN creates a basis for the development of high-level software using NONMEM as the regression tool.

  • 97.
    Lindbom, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wilkins, Justin J
    Frey, Nicolas
    Karlsson, Mats O
    Jonsson, E Niclas
    Evaluating the evaluations: resampling methods for determining model appropriateness in pharmacometric data analysisManuscript (Other academic)
  • 98.
    Lindell, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Variable Expression of CYP and Pgp Genes in the Human Small Intestine2003In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 33, no 6, p. 493-499Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome p450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes.

    METHODS:

    The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed.

    RESULTS:

    Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively.

    CONCLUSIONS:

    Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation.

  • 99.
    Linderson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Integrated database used to develop a population growth rate model for young females with Turner Syndrome2012Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Integrated database used to develop a population growth rate model in young females with Turner Syndrome

     

    Sara Linderson

     

    Supervisor: Dr. Jan Freijer, research director PK/PD at Centre of Human Drug Research, The Netherlands,

    Degree Project in Pharmacokinetics D, 30 credits,

    Examiner: Dr. Margareta Hammarlund-Udenaes, Faculty of Pharmacy, Uppsala University

     

    Introduction: Girls with the chromosomal disorder Turner Syndrome (TS) reach an adult stature 20 cm less than average healthy growing girls. In treatment of TS, growth hormone, estrogens and androgens are thought to enhance growth. However, it remains unclear what the optimal doses are and when they should be initiated and halted. Optimization of treatment can be supported using a growth model that includes the effect of treatment in different stages of growth.

    Aim: To continue the development of a population mixed effects model based on growth rate that will be used in research of treatment effects. Secondly, to create an integrated database that supports the modeling of treatment effects in girls with TS.

    Materials and Methods: Different datasets were merged into a database. Height data from the datasets was used in calculation of growth rate. Both height and growth rate was used in modeling.

    Results: A large integrative database with uniform coding and variable names was created. Data for no treatment and treatment was simultaneously used in modeling of the population growth rate model. The model was built on three growth stages representing infancy, childhood and puberty. Each of the stages described the growth rate well and could predict height correctly, but only if a combination of height and growth rate was used in the modeling. A clear treatment effect of x cm height gain can be quantified by the model.

    Conclusions: The developed population mixed effects model based on growth rate is an suitable tool in future researches of treatment effects in girls with TS, with the awareness that height and growth rate should be combined in the model. Treatment effects can be studied in more detail by using database information.

  • 100.
    Lindhagen, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Vig-Hjarnaa, Pernille
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Latini, Scilla
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Pharmacodynamic differences between species exemplified by the novel anticancer agent CHS 8282004In: Drug development research, ISSN 0272-4391, E-ISSN 1098-2299, Vol. 61, no 4, p. 218-226Article in journal (Refereed)
    Abstract [en]

    When a candidate drug enters clinical trials, decisions regarding dosing are mainly based on animal data. Occasionally, toxicity problems are faced in the clinic because of unexpected species differences in pharmacokinetics or pharmacodynamics between humans and preclinical species. Fludarabine and topotecan are examples of such drugs. In the first clinical trials of the new agent CHS 828, the maximum tolerated dose was reached earlier than expected from animal data. This paper discusses the issue of species differences in the development of anticancer drugs, and preclinical models for detection and quantification of such differences. Pharmacokinetic and hematological toxicity data of CHS 828 from studies in rats and humans are presented. In vitro sensitivity to CHS 828 and some established cytotoxic agents was measured in lymphocytes from humans and rats and in a panel of human and rodent cell-lines. 10–100 times higher CHS 828 exposure was tolerated by rats than by patients. In both in vitro cell systems, CHS 828 showed higher potency in human cells compared to rodent cells. A species difference was evident also for fludarabine, but not for doxorubicin and cisplatin. CHS 828 pharmacokinetics were similar across species. In conclusion, the lower tolerance of CHS 828 in humans than in rats could be detected in vitro in cultures of peripheral lymphocytes. Preclinical studies of species differences could help the interpretation of in vivo effect studies as well as the choice of starting dose for clinical trials. We suggest peripheral lymphocytes from different species as a potential model system for such studies.

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