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  • 51.
    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.

  • 52.
    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.

  • 53.
    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.

  • 54.
    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.

  • 55.
    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.

  • 56.
    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
  • 57. 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.

  • 58.
    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)
  • 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
    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.

  • 60. 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.

  • 61.
    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.

  • 62.
    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.

  • 63.
    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.

  • 64.
    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. 

  • 65.
    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.

  • 66.
    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.  

  • 67.
    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.

  • 68.
    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.

  • 69.
    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.

  • 70.
    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.

  • 71. 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.

  • 72.
    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.

  • 73.
    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
  • 74.
    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.

  • 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.
    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.

  • 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 (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.

  • 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.
    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.

  • 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.
    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.

  • 79.
    Jönsson, Siv