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  • 1. Ahn, Jae Eun
    et al.
    Plan, Elodie L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Miller, Raymond
    Modeling longitudinal daily seizure frequency data from pregabalin add-on treatment2012In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, no 6, p. 880-892Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to describe longitudinal daily seizure count data with respect to the effects of time and pregabalin add-on therapy. Models were developed in step-wise manner: base model, time effect model, and time and drug effect (final) model, using a negative binomial distribution with Markovian features. Mean daily seizure count (λ) was estimated to be 0.385 (RSE 3.09%) and was further increased depending on the seizure count on the previous day. An overdispersion parameter (OVDP), representing extra-Poisson variation, was estimated to be 0.330 (RSE 11.7%). Inter-individual variances on λ and OVDP were 84.7% and 210%, respectively. Over time, λ tended to increase exponentially with a rate constant of 0.272 year-1 (RSE 26.8%). A mixture model was applied to classify responders/non-responders to pregabalin treatment. Within the responders, λ decreased exponentially with respect to dose with a constant of 0.00108 mg-1 (RSE 11.9%). The estimated responder rate was 66% (RSE 27.6%). Simulation-based diagnostics showed the model reasonably reproduced the characteristics of observed data. Highly variable daily seizure frequency was successfully characterized incorporating baseline characteristics, time effect, and the effect of pregabalin with classification of responders/non-responders, all of which are necessary to adequately assess the efficacy of antiepileptic drugs.

     

  • 2.
    Alskär, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bagger, Jonatan I
    Røge, Rikke M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Knop, Filip K
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vilsbøll, Tina
    Kjellsson, Maria C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes2016In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 56, no 3, p. 340-348Article in journal (Refereed)
    Abstract [en]

    The integrated glucose-insulin (IGI) model is a previously published semi-mechanistic model, which describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work was to use knowledge of physiology to improve the IGI model's description of glucose absorption and gastric emptying after tests with varying glucose doses. The developed model's performance was compared to empirical models. To develop our model, data from oral and intravenous glucose challenges in patients with type 2 diabetes and healthy control subjects were used together with present knowledge of small intestinal transit time, glucose inhibition of gastric emptying and saturable absorption of glucose over the epithelium to improve the description of gastric emptying and glucose absorption in the IGI model. Duodenal glucose was found to inhibit gastric emptying. The performance of the saturable glucose absorption was superior to linear absorption regardless of the gastric emptying model applied. The semi-physiological model developed performed better than previously published empirical models and allows for better understanding of the mechanisms underlying glucose absorption. In conclusion, our new model provides a better description and improves the understanding of dynamic glucose tests involving oral glucose.

  • 3. Alskär, Oskar
    et al.
    Bagger, Jonatan
    Røge, Rikke Meldgaard
    Knop, Filip
    Karlsson, Mats
    Vilsbøll, Tina
    Kjellsson, Maria
    Semimechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes2015In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604Article in journal (Refereed)
  • 4.
    Bergman, Ebba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, Elin M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect of a Single Gemfibrozil Dose on the Pharmacokinetics of Rosuvastatin in Bile and Plasma in Healthy Volunteers2010In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 50, no 9, p. 1039-1049Article in journal (Refereed)
    Abstract [en]

    The effect of a single intrajejunal dose of gemfibrozil (600 mg) on the plasma pharmacokinetics and biliary excretion of a single intrajejunal dose of rosuvastatin (20 mg) was investigated by using a multichannel catheter positioned in the distal duodenum/proximal jejunum in eight healthy volunteers. Bile and plasma samples were collected every 20 min for 200 min, with additional plasma samples being withdrawn for up to 48 hrs. Gemfibrozil did not affect the bioavailability of rosuvastatin, although it increased the apparent absorption phase during the initial 200 minutes (AUC0-200) by 1.56-fold (95%CI: 1.14-2.15). The interaction was less pronounced in this single dose study than in a previous report when gemfibrozil was administered repeatedly, nevertheless, the interaction coincided with the highest exposure to gemfibrozil. The plausible reason why the interaction in this investigation was only minor is the low exposure to gemfibrozil (and its metabolites), suggesting that the total plasma concentration of gemfibrozil needs to be above 20 µM in order to affect the disposition of rosuvastatin. This study demonstrates the value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation.

  • 5. Chaurasia, Chandra S.
    et al.
    Müller, Markus
    Bashaw, Edward D.
    Benfeldt, Eva
    Bolinder, Jan
    Bullock, Ross
    Bungay, Peter M.
    DeLange, Elizabeth C. M.
    Derendorf, Hartmut
    Elmquist, William F.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Joukhadar, Christian
    Kellogg, Dean L.
    Lunte, Craig E.
    Nordström, Carl Henrik
    Rollema, Hans
    Sawchuk, Ronald J.
    Cheung, Belinda W. Y.
    Shah, Vinod P.
    Stahle, Lars
    Ungerstedt, Urban
    Welty, Devin F.
    Yeo, Helen
    AAPS-FDA Workshop White Paper: microdialysis principles, application, and regulatory perspectives2007In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 5, p. 589-603Article in journal (Refereed)
    Abstract [en]

    Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (μD) is the only tool available that explicitly provides data on the extracellular space. Although μD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of μD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of μD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on μD as a tool in drug research and development.

  • 6.
    Fanta, Samuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Niemi, Mikko
    Holmberg, Christer
    Hoppu, Kalle
    Backman, Janne T.
    Long-Term Changes in Cyclosporine Pharmacokinetics After Renal Transplantation in Children: Evidence for Saturable Presystemic Metabolism and Effect of NR1I2 Polymorphism2010In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 50, no 5, p. 581-597Article in journal (Refereed)
    Abstract [en]

    To improve cyclosporine dose individualization, the authors carried out a comprehensive analysis of the effects of clinical and genetic factors on cyclosporine pharmacokinetics in 176 children before and up to 16 years after renal transplantation. Pretransplantation test doses of cyclosporine were given intravenously and orally, followed by blood sampling for 24 hours. After transplantation, cyclosporine was quantified at trough, 2 hours postdose, or with dose-interval curves. A 3-compartment population pharmacokinetic model was used to describe the data. Cyclosporine oral bioavailability increased more than 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1 to 1.5 years. Moreover, older children receiving cyclosporine twice daily as the gelatin capsule microemulsion formulation had an about 1.25 to 1.3 times higher bioavailability than did the younger children receiving the liquid formulation thrice daily. In 91 children with genetic data after transplantation, patients carrying the NR1I2 g.-25385C-g.-24381A-g.205_-200GAGAAG-g.7635G-g.8055C haplotype had about one-tenth lower bioavailability, per allele, than did non-carriers (P = .039). The significance of the NR1I2 genotype warrants further study. In conclusion, by accounting for the effects of developmental factors (body weight), time after transplantation, and cyclosporine dosing frequency/formulation, it may be possible to improve individualization of cyclosporine dosing in children.

  • 7. Gupta, Pankaj
    et al.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Krishnaswami, Sriram
    French, Jonathan
    A Semi-Mechanistic Model of CP-690,550-Induced Reduction in Neutrophil Counts in Patients With Rheumatoid Arthritis2010In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 50, no 6, p. 679-687Article in journal (Refereed)
    Abstract [en]

    CP-690,550, a selective inhibitor of the Janus kinase family, is being developed as an oral disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). A semi-mechanistic model was developed to characterize the time course of drug-induced absolute neutrophil count (ANC) reduction in a phase 2a study. Data from 264 RA patients receiving 6-week treatment (placebo, 5, 15, 30 mg bid) followed by a 6-week off-treatment period were analyzed. The model included a progenitor cell pool, a maturation chain comprising transit compartments, a circulation pool, and a feedback mechanism. The model was adequately described by system parameters (BASEh, ktrh, gamma, and kcirc), disease effect parameters (DIS), and drug effect parameters (koff and kD). The disease manifested as an increase in baseline ANC and reduced maturation time due to increased demand from the inflammation site. The drug restored the perturbed system parameters to their normal values via an indirect mechanism. ANC reduction due to a direct myelosuppressive drug effect was not supported. The final model successfully described the dose- and time-dependent changes in ANC and predicted the incidence of neutropenia at different doses reasonably well.

  • 8.
    Hamrén, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Öhman, K Peter
    Svensson, Maria K
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacokinetic-Pharmacodynamic Assessment of the Interrelationships Between Tesaglitazar Exposure and Renal Function in Patients With Type 2 Diabetes Mellitus2012In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, no 9, p. 1317-1327Article in journal (Refereed)
    Abstract [en]

    The effects of tesaglitazar on renal function (assessed as urinary clearance of 125I-sodium iothalamate or estimated by the modification of diet in renal disease formula) were studied in a 24-week open-label trial in type 2 diabetes mellitus patients randomized to daily doses of either tesaglitazar 2 mg or pioglitazone 45 mg. The aim of the analysis was to develop a population pharmacokinetic-pharmacodynamic model that could simultaneously describe the interrelationship between tesaglitazar exposure and reduction in renal function over time in patients with type 2 diabetes mellitus. The pharmacokinetic-pharmacodynamic model could adequately describe the interplay between tesaglitazar and glomerular filtration rate. A one-compartment model in which the apparent clearance was influenced by glomerular filtration rate characterized the pharmacokinetics of tesaglitazar. An indirect-response model was used for the slow time course of change in glomerular filtration rate, which decreased from 100 to 78 mL/min/1.73m2 after 12 weeks of treatment. All tesaglitazar-treated patients had a reduction in glomerular filtration rate, and available demographic variables could not explain differences in response. Patients treated with an angiotensin converting enzyme inhibitor were more sensitive to tesaglitazar and had larger glomerular filtration rate decrease compared to nontreated patients. Approximately 8 weeks after discontinuing treatment, mean glomerular filtration rate had returned towards baseline. The model and data give valuable insights into the dynamic changes in glomerular filtration rate over time.

  • 9.
    Hennig, Stefanie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fanta, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Backman, Janne T.
    Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Hoppu, Kalle
    Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Hooker, Andrew C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Application of the Optimal Design Approach to Improve a Pretransplant Drug Dose Finding Design for Ciclosporin2012In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, no 3, p. 347-360Article in journal (Refereed)
    Abstract [en]

    A time and sampling intensive pretransplant test dose design was to be reduced, but at the same time optimized so that there was no loss in the precision of predicting the individual pharmacokinetic (PK) estimates of posttransplant dosing. The following variables were optimized simultaneously: sampling times, ciclosporin dose, time of second dose, infusion duration, and administration order, using a published ciclosporin population PK model as prior information. The original design was reduced from 22 samples to 6 samples/patient and both doses (intravenous oral) were administered within 8 hours. Compared with the prior information given by the published ciclosporin population PK model, the expected standard deviations (SDs) of the individual parameters for clearance and bioavailability could be reduced by, on average, 40% under the optimized sparse designs. The gain of performing the original rich design compared with the optimal reduced design, considering the standard errors of the parameter estimates, was found to be minimal. This application demonstrates, in a practical clinical scenario, how optimal design techniques may be used to improve diagnostic procedures given available software and methods.

  • 10.
    Hennig, Stefanie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hooker, Andrew C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Trial treatment length optimization with an emphasis on disease progression studies2009In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 49, no 3, p. 323-335Article in journal (Refereed)
    Abstract [en]

    Optimal design has been used in the past mainly to optimize sampling schedules for clinical trials. Optimization on design variables other than sampling times has been published in the literature only once before. This study shows, as an example, optimization on the length of treatment periods to obtain reliable estimates of drug effects on longterm disease progression studies. Disease progression studies are high in cost, effort, and time; therefore, optimization of treatment length is highly recommended to avoid failure or loss of information. Results are provided for different drug effects (eg, protective and symptomatic) and for different lengths of studies and sampling schedules. The merits of extending the total study length versus inclusion of more samples per participants are investigated. The authors demonstrate that if no observations are taken during the washout period, a trial can lose up to 40% of its efficiency. Furthermore, when optimization of treatment length is performed using multiple possible drug effect models simultaneously, these studies show high power in discriminating between different drug effect models.

  • 11.
    Jauslin, Petra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Frey, Nicolas
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Modeling of 24-Hour Glucose and Insulin Profiles of Patients With Type 2 Diabetes2011In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 51, no 2, p. 153-164Article in journal (Refereed)
    Abstract [en]

    A model able to simultaneously characterize and simulate 24-hour glucose and insulin profiles following multiple meal tests was developed, extending an integrated glucose-insulin model for oral glucose tolerance tests that was previously published. The analysis was based on glucose and insulin measurements from 59 placebo-treated patients with type 2 diabetes. Circadian variations in glucose homeostasis were assessed on relevant parameters based on literature review. They were best described by a nighttime dip in insulin secretion between approximately 9 p.m. and 5 a.m. using a modulator function. The integrated glucose-insulin model has thus been shown to be applicable to real-life situations determined by multiple meals over the course of a day. This provides the basis for the analysis and simulation of long-term glucose and insulin data. The model may also prove useful for understanding antidiabetic drug actions and requirements in the context of circadian changes in glucose-insulin regulation.

  • 12.
    Jauslin, Petra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Frey, Nicolas
    Identification of the Mechanism of Action of a Glucokinase Activator From Oral Glucose Tolerance Test Data in Type 2 Diabetic Patients Based on an Integrated Glucose-Insulin Model2012In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, no 12, p. 1861-1871Article in journal (Refereed)
    Abstract [en]

    A mechanistic drug-disease model was developed on the basis of a previously published integrated glucose-insulin model by Jauslin et al. A glucokinase activator was used as a test compound to evaluate the model’s ability to identify a drug’s mechanism of action and estimate its effects on glucose and insulin profiles following oral glucose tolerance tests. A kinetic-pharmacodynamic approach was chosen to describe the drug’s pharmacodynamic effects in a dose-response-time model. Four possible mechanisms of action of antidiabetic drugs were evaluated, and the corresponding affected model parameters were identified: insulin secretion, glucose production, insulin effect on glucose elimination, and insulin-independent glucose elimination. Inclusion of drug effects in the model at these sites of action was first tested one-by-one and then in combination. The results demonstrate the ability of this model to identify the dual mechanism of action of a glucokinase activator and describe and predict its effects: Estimating a stimulating drug effect on insulin secretion and an inhibiting effect on glucose output resulted in a significantly better model fit than any other combination of effect sites. The model may be used for dose finding in early clinical drug development and for gaining more insight into a drug candidate’s mechanism of action.

  • 13.
    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.

  • 14.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Miller, Raymond
    Daiichi Sankyo Pharma Dev, Edison, NJ USA..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study2015In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 55, no 11, p. 1268-1279Article in journal (Refereed)
    Abstract [en]

    A model characterizing the population pharmacokinetics (PK) of edoxaban and its major metabolite, M4, following a single oral dose of 15mg administered to subjects with varying kidney function was developed. Thirty-two subjects contributed with edoxaban plasma, edoxaban urine, and M4 plasma concentrations. Edoxaban urine concentrations allowed estimation of renal clearance, and high contribution of renal to total clearance enabled estimation of absolute oral bioavailability. A 2-compartment model with delayed absorption and elimination parameterized as renal clearance linearly related to creatinine clearance (CLcr) and nonrenal clearance forming M4 described edoxaban PK. The PK of M4 was described with a 1-compartment model. For a typical subject (70kg; CLcr, 100mL/min) bioavailability, clearance, and central and peripheral volume of distribution for edoxaban was estimated to 72.3%, 21.0 L/h, 95.4 L, and 54.3 L, respectively. For both edoxaban and M4, the model predicted systemic exposure to increase 57.0%, 35.0%, and 11.6% in a subject having CLcr of 30, 50, and 80mL/min, respectively, compared with a subject having a CLcr of 100mL/min. Concentration ratios (M4 over edoxaban) were predicted to vary with time after dose, but with minor influence of kidney function and body weight. Results were in agreement with previous analyses.

  • 15.
    Kjellsson, Maria C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cosson, Valerie F.
    Mazer, Norman A.
    Frey, Nicolas
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Model-Based Approach to Predict Longitudinal HbA1c, Using Early Phase Glucose Data From Type 2 Diabetes Mellitus Patients After Anti-Diabetic Treatment2013In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 53, no 6, p. 589-600Article in journal (Refereed)
    Abstract [en]

    Predicting late phase outcomes from early-phase findings can help inform decisions in drug development. If the measurements in early-phase differ from those in late phase, forecasting is more challenging. In this paper, we present a model-based approach for predicting glycosylated hemoglobin (HbA1c) in late phase using glucose and insulin concentrations from an early-phase study, investigating an anti-diabetic treatment. Two previously published models were used; an integrated glucose and insulin (IGI) model for meal tolerance tests and an integrated glucose-red blood cell-HbA1c (IGRH) model predicting the formation of HbA1c from the average glucose concentration (Cg,av). Output from the IGI model was used as input to the IGRH model. Parameters of the IGI model and drug effects were estimated using data from a phase1 study in 59 diabetic patients receiving various doses of a glucokinase activator. Cg,av values were simulated according to a Phase 2 study design and used in the IGRH model for predictions of HbA1c. The performance of the model-based approach was assessed by comparing the predicted to the actual outcome of the Phase 2 study. We have shown that this approach well predicts the longitudinal HbA1c response in a 12-week study using only information from a 1-week study where glucose and insulin concentrations were measured.

  • 16. Kleber, Franz X.
    et al.
    Bollmann, Tom
    Borst, Mathias M.
    Costard-Jäckle, Angelika
    Ewert, Ralf
    Kivikko, Matti
    Petterson, Tiina
    Pohjanjousi, Pasi
    Sonntag, Steffen
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: results of a pilot study2009In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 49, no 1, p. 109-115Article in journal (Refereed)
  • 17.
    Lledó-García, Rocío
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hennig, Stefanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hooker, Andrew C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ethically Attractive Dose-Finding Designs for Drugs With a Narrow Therapeutic Index2012In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, no 1, p. 29-38Article in journal (Refereed)
    Abstract [en]

    A simulation-based comparison study on the relative merits of dose-control trials (DCTs) with exposure-response analysis versus concentration-control trials (CCTs) for drugs with narrow therapeutic index showed that DCT designs are more informative about the exposure-response relationship. The authors revisit the question employing optimal design methodology and propose strategies for designing ethically attractive trials for these drugs, balancing between individual-collective risk and informativeness. An optimal study was performed considering a hypothetical immunosuppressant agent with 2 clinical end points. Different scenarios were optimized applying cost-based designs (unwanted events vs number of sub-jects/trial or maximal individual risk). Dose/exposure targets and number of subjects per trial/arm were optimized. Prior information inclusion on baseline risks was evaluated. DCTs were more informative, needing smaller studies to provide the same information as CCTs. Using the number of unwanted events-rather than subjects-as cost resulted in ethically more attractive designs. Including prior baseline risk information reduced the number of subject/events and allowed the use of targets closer to the optimal. Designing dose-finding trials for some narrow therapeutic index drugs may be improved by using DCTs with exposure-response analysis, cost-based designs, prior information, and optimal design analysis providing information on the ethical trade-off between individual risk and information gain.

  • 18.
    Maloney, Alan
    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.
    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.
    Optimal adaptive design in clinical drug development: a simulation example2007In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 10, p. 1231-1243Article in journal (Refereed)
    Abstract [en]

    The objective of this article is to demonstrate optimal adaptive design as a methodology for improving the performance of phase II dose-response studies. Optimal adaptive design uses both information prior to the study and data accrued during the study to continuously update and refine the study design. Dose-response models include linear, log-linear, 4-parameter sigmoidal E-max, and exponential models. Where the response has both a placebo effect and plateau at higher doses, only the 4-parameter sigmoidal E-max model behaves acceptably and hence is used to illustrate the methodology. Across 13 hypothetical dose-response scenarios considered, it was shown that the capability of the adaptive designs to "learn" the true dose response resulted in performances up to 180% more efficient than the best fixed optimal designs, This work exposes the common misconception that adaptive designs are somehow "risky." As shown in this simple simulation example, the converse is true. Adaptive designs perform extremely well both when prior information is accurate and inaccurate. This leads to improved dose-response models and dose selection in phase III. This benefits sponsors, regulators, and subjects alike by reducing sample size, increasing information, and providing better dose guidance.

  • 19.
    Matsson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Eriksson, Ulf
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hoffmann, Kurt-Jurgen
    Logren, Ulrika
    Fridblom, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Petri, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Biliary Excretion of Ximelagatran and Its Metabolites and the Influence of Erythromycin Following Intraintestinal Administration to Healthy Volunteers2011In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 51, no 5, p. 770-783Article in journal (Refereed)
    Abstract [en]

    The biliary excretion of the oral thrombin inhibitor ximelagatran and its metabolites was investigated by using duodenal aspiration in healthy volunteers following intraintestinal dosing. In the first investigation, radiolabeled [C-14] ximelagatran was administered, enabling quantification of the biliary excretion and identification of metabolites in the bile. In the second study, the effect of erythromycin on the biliary clearance of ximelagatran and its metabolites was investigated to clarify the reported ximelagatran-erythromycin interaction. Approximately 4% of the intraintestinal dose was excreted into bile with ximelagatran and its active form, melagatran, being the most abundant compounds. Four novel ximelagatran metabolites were identified in bile (< 0.1% of dose). Erythromycin changed the pharmacokinetics of ximelagatran and its metabolites, with an elevated ximelagatran (78% increase), OH-melagatran (89% increase), and melagatran (86% increase) plasma exposure and higher peak plasma concentrations of the compounds being measured. In parallel, the biliary clearance was moderately reduced. The results suggest that inhibition of hepatobiliary transport is a likely mechanism for the interaction between erythromycin and ximelagatran. Furthermore, the study demonstrated the value of direct bile sampling in humans for the identification of primary biliary metabolites.

  • 20.
    Nielsen, Elisabet I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Al-Saqi, Shahla H.
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Jonasson, Aino F.
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Uvnäs-Moberg, Kerstin
    Swedish Univ Agr Sci, Dept Anim Environm & Hlth, Skara, Sweden..
    Population Pharmacokinetic Analysis of Vaginally and Intravenously Administered Oxytocin in Postmenopausal Women2017In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 57, no 12, p. 1573-1581Article in journal (Refereed)
    Abstract [en]

    Oxytocin is a neuropeptide hormone used clinically for more than 50 years due to its ability to induce uterine contractions and milk ejection. Vagitocin is a vaginal oxytocin gel developed as a potential treatment of vaginal atrophy in postmenopausal women. The aim of this study was to characterize the oxytocin pharmacokinetics following vaginal and intravenous administration in postmenopausal women. Data from 33 participants enrolled in 2 clinical studies were used in the analysis, with a total of 651 observed oxytocin plasma concentrations, of which 78 were baseline observations, 178 observations following intravenous administration (10 IU), and 395 observations following vaginal administration (100 or 400 IU). The population pharmacokinetics of oxytocin was described using a 2-compartment disposition model with a flexible parallel absorption model accounting for double-peak profiles following vaginal administration. The clearance, volume of distribution at steady state, distribution half-life, and terminal half-life were estimated to be 27 L/h, 15 L, 5.5 minutes, and 1.2 hours, respectively. The bioavailability following vaginal administration was estimated to be 2.5% for the typical patient, but with considerable variability both between individuals (interindividual variability of 374%) and between occasions (interoccasion variability of 79%). The data and the developed model add new and important information as to the clinical pharmacokinetics of oxytocin.

  • 21.
    Novakovic, Ana M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Merck KGaA, Pharmacometry, Darmstadt, Germany.
    Thorsted, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schindler, Emilie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Munafo, A.
    Merck Inst Pharmacometr, Lausanne, Switzerland.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacometric Analysis of the Relationship Between Absolute Lymphocyte Count and Expanded Disability Status Scale and Relapse Rate, Efficacy End Points, in Multiple Sclerosis Trials2018In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 58, no 10, p. 1284-1294Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to assess the relationship between the absolute lymphocyte count (ALC), and disability (as measured by the Expanded Disability Status Scale [EDSS]) and occurrence of relapses, 2 efficacy endpoints, respectively, in patients with remitting-relasping multiple sclerosis. Data for ALC, EDSS, and relapse rate were available from 1319 patients receiving placebo and/or cladribine tablets. Pharmacodynamic models were developed to characterize the time course of the endpoints. ALC-related measures were then evaluated as predictors of the efficacy endpoints. EDSS data were best fitted by a model where the logit-linear disease progression is affected by the dynamics of ALC change from baseline. Relapse rate data were best described by the Weibull hazard function, and the ALC change from baseline was also found to be a significant predictor of time to relapse. Presented models have shown that once cladribine exposure driven ALC-derived measures are included in the model, the need for drug effect components is of less importance (EDSS) or disappears (relapse rate). This simplifies the models and theoretically makes them mechanism specific rather than drug specific. Having a reliable mechanism-specific model would allow leveraging historical data across compounds, to support decision making in drug development and possibly shorten the time to market.

  • 22.
    Quartino, Angelica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Freijs, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jonsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kristensen, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Modeling of in vitro drug activity and prediction of clinical outcome in acute myeloid leukemia2007In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 8, p. 1014-1021Article in journal (Refereed)
    Abstract [en]

    The objectives of this study were to develop a population pharmacodynamic model describing the in vitro drug sensitivity of tumor cells and to relate in vitro parameters to clinical outcome. Cell samples from 179 patients with acute myelocytic leukemia were exposed to cytosine arabinoside and daunorubicin, and cytotoxicity was analyzed using the fluorometric microculture cytotoxicity assay. A sigmoid E(max)-model for daunorubicin and an E(max)-model for cytosine arabinoside described the data. The model predicted drug potency (EC(50)) adequately from 1 concentration measurement. A logistic regression on individual in vitro parameters of 46 patients treated with the daunorubicin plus cytosine arabinoside regimen showed that the probability of complete response was significantly (P < .05) related to the product of the E(max)/EC(50) ratio of the two drugs. The findings demonstrate the value of population pharmacodynamic modeling of in vitro drug sensitivity data and a significant relationship between the in vitro parameters and clinical outcome.

  • 23. Rayner, Craig R.
    et al.
    Chanu, Pascal
    Gieschke, Ronald
    Boak, Lauren M.
    Jonsson, E Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of oseltamivir when coadministered with probenecid.2008In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 48, no 8, p. 935-947Article in journal (Refereed)
    Abstract [en]

    Oseltamivir is a potent, selective, oral neuraminidase inhibitor for the treatment and prophylaxis of influenza. Plasma concentrations of the active metabolite, oseltamivir carboxylate, are increased in the presence of probenecid, suggesting that the combination could allow for the use of reduced doses of oseltamivir. To investigate this proposal, we developed a population pharmacokinetic model and simulated the pharmacokinetics of candidate combination regimens of oral oseltamivir (45 mg and 30 mg twice a day) plus oral probenecid (500 mg/6 hourly). Probenecid plus oseltamivir 45 mg achieved all the pharmacokinetic parameters expected of oseltamivir alone, but combination with oseltamivir 30 mg and dose interval extension approaches did not. An oseltamivir-probenecid combination may compromise tolerability and enhance the potential for drug interactions. In addition, increased dosing requirements may affect compliance and attainment of optimal oseltamivir exposure, potentially facilitating the emergence of viral strains with reduced susceptibility to oseltamivir. These factors, set alongside increased capacity for oseltamivir production, should be carefully considered before an oseltamivir-probenecid combination is used.

  • 24.
    Ribbing, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hamrén, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Maria K.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Model for Glucose, Insulin, and Beta-Cell Dynamics in Subjects With Insulin Resistance and Patients With Type 2 Diabetes2010In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 50, no 8, p. 861-872Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes mellitus (T2DM) is a progressive, metabolic disorder characterized by reduced insulin sensitivity and loss of beta-cell mass (BCM), resulting in hyperglycemia. Population pharmacokinetic-pharmacodynamic (PKPD) modeling is a valuable method to gain insight into disease and drug action. A semi-mechanistic PKPD model incorporating fasting plasma glucose (FPG), fasting insulin, insulin sensitivity, and BCM in patients at various disease stages was developed. Data from 3 clinical trials (phase II/III) with a peroxisome proliferator-activated receptor agonist, tesaglitazar, were used to develop the model. In this, a modeling framework proposed by Topp et al was expanded to incorporate the effects of treatment and impact of disease, as well as variability between subjects. The model accurately described FPG and fasting insulin data over time. The model included a strong relation between insulin clearance and insulin sensitivity, predicted 40% to 60% lower BCM in T2DM patients, and realistic improvements of BCM and insulin sensitivity with treatment. The treatment response on insulin sensitivity occurs within the first weeks, whereas the positive effects on BCM arise over several months. The semi-mechanistic PKPD model well described the heterogeneous populations, ranging from nondiabetic, insulin-resistant subjects to long-term treated T2DM patients. This model also allows incorporation of clinical-experimental studies and actual observations of BCM.

  • 25. Rikke, Meldgaard Røge
    Modeling of 24-Hour Glucose and Insulin Profiles in Patients With Type 2 Diabetes Mellitus Treated With Biphasic Insulin Aspart2014In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604Article in journal (Refereed)
  • 26.
    Røge, Rikke M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Klim, Søren
    Kristensen, Niels R
    Ingwersen, Steen H
    Kjellsson, Maria C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Modeling of 24-Hour Glucose and Insulin Profiles in Patients With Type 2 Diabetes Mellitus Treated With Biphasic Insulin Aspart2014In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 54, no 7, p. 809-817Article in journal (Refereed)
    Abstract [en]

    Insulin therapy for diabetes patients is designed to mimic the endogenous insulin response of healthy subjects and thereby generate normal blood glucose levels. In order to control the blood glucose in insulin-treated diabetes patients, it is important to be able to predict the effect of exogenous insulin on blood glucose. A pharmacokinetic/pharmacodynamic model for glucose homoeostasis describing the effect of exogenous insulin would facilitate such prediction. Thus the aim of this work was to extend the previously developed integrated glucose-insulin (IGI) model to predict 24-hour glucose profiles for patients with Type 2 diabetes following exogenous insulin administration. Clinical data from two trials were included in the analysis. In both trials, 24-hour meal tolerance tests were used as the experimental setup, where exogenous insulin (biphasic insulin aspart) was administered in relation to meals. The IGI model was successfully extended to include the effect of exogenous insulin. Circadian variations in glucose homeostasis were assessed on relevant parameters, and a significant improvement was achieved by including a circadian rhythm on the endogenous glucose production in the model. The extended model is a useful tool for clinical trial simulation and for elucidating the effect profile of new insulin products.

  • 27. Røge, Rikke Meldgaard
    Modeling of 24-hour glucose and insulin profiles in patients with type 2 diabetes mellitus treated with biphasic insulin aspart.2014In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 54, no 7, p. 809-817Article in journal (Refereed)
  • 28.
    Silber, Hanna E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Frey, Nicolas
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    An integrated glucose-insulin model to describe oral glucose tolerance test data in healthy volunteers2010In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 50, no 3, p. 246-256Article in journal (Refereed)
    Abstract [en]

    The extension of the previously developed integrated models for glucose and insulin (IGI) to include the oral glucose tolerance test (OGTT) in healthy volunteers could be valuable to better understand the differences between healthy individuals and those with type 2 diabetes mellitus (T2DM). Data from an OGTT in 23 healthy volunteers were used. Analysis was based on the previously developed intravenous model with extensions for glucose absorption and incretin effect on insulin secretion. The need for additional structural components was evaluated. The model was evaluated by simulation and a bootstrap. Multiple glucose and insulin concentration peaks were observed in most individuals as well as hypoglycemic episodes in the second half of the experiment. The OGTT data were successfully described by the extended basic model. An additional control mechanism of insulin on glucose production improved the description of the data. The model showed good predictive properties, and parameters were estimated with good precision. In conclusion, a previously presented integrated model has been extended to describe glucose and insulin concentrations in healthy volunteers following an OGTT. The characterization of the differences between the healthy and diabetic stages in the IGI model could potentially be used to extrapolate drug effect from healthy volunteers to T2DM.

     

  • 29.
    Silber, Hanna E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jauslin, Petra M
    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.
    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 model for glucose and insulin regulation in healthy volunteers and type 2 diabetic patients following intravenous glucose provocations2007In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 9, p. 1159-1171Article in journal (Refereed)
    Abstract [en]

    An integrated model for the regulation of glucose and insulin concentrations following intravenous glucose provocations in healthy volunteers and type 2 diabetic patients was developed. Data from 72 individuals were included. Total glucose, labeled glucose, and insulin concentrations were determined. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed in NONMEM. Integrated models for glucose, labeled glucose, and insulin were developed. Control mechanisms for regulation of glucose production, insulin secretion, and glucose uptake were incorporated. Physiologically relevant differences between healthy volunteers and patients were identified in the regulation of glucose production, elimination rate of glucose, and secretion of insulin. The model was able to describe the insulin and glucose profiles well and also showed a good ability to simulate data. The features of the present model are likely to be of interest for analysis of data collected in antidiabetic drug development and for optimization of study design.

  • 30. Strid, Stig
    et al.
    Nilsson, Dag
    Borgå, Olof
    Wemer, Johan
    Grahnén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    NXY-059 does not significantly interact with furosemide in healthy volunteers2006In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 46, no 12, p. 1417-1425Article in journal (Refereed)
    Abstract [en]

    NXY-059 is a free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. Acute ischemic stroke patients receiving NXY-059 may also be exposed to diuretics for treatment of heart failure or hypertension. NXY-059 and furosemide are partly eliminated by active tubular secretion via an organic anion transporter. This double-blind, randomized, crossover, placebo-controlled study investigated whether an infusion of NXY-059 (15 mg/mL) during 12 hours affects the diuretic and saluretic effects of a 30-mg intravenous bolus dose of furosemide (10 mg/mL) administered after 6 hours' infusion, in 13 male and 11 female healthy subjects. The net increase in urine volume and sodium excretion in the interval of 6 to 12 hours was 4.15 L and 178 mmol/L, respectively, during NXY-059 treatment (P = .93) and 4.34 L and 190 mmol/L, respectively, during placebo treatment (P = .54). NXY-059 reduced the renal clearance of furosemide by 19% (P = .019), and furosemide reduced the renal clearance of NXY-059 by 8% (P = .005). NXY-059 was well tolerated.

  • 31.
    Viberg, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Estimation of cefuroxime dosage using pharmacodynamic targets, MIC distributions, and minimization of a risk function2008In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 48, no 11, p. 1270-81Article in journal (Refereed)
    Abstract [en]

    An approach for estimation of dosing strategies based on data-derived models and assessment of the risk associated with deviation from the treatment target is presented. The work is illustrated by establishing a dosing strategy to be used for a priori individualization on the basis of renal function for the antibiotic cefuroxime. Treatment involved exposing patients to concentrations above the minimum inhibitory concentration (MIC) for 50% of the dosing interval. The risk (penalty) function incorporated both deviations from the target and the use of excess amount of drug. Dosing strategies were estimated for a target population by minimizing the risk function. The population was characterized by a population pharmacokinetic model, and distributions of CLcr and body weight were reflective of the target group. The estimated dosing strategies were assessed by evaluating population distributions of (1) percentage of dosing interval with concentrations above MIC, (2) time of drug exposure below MIC, and (3) drug administered in excess to reach the target. These distributions were generated using wild-type MIC distributions for Escherichia coli and Streptococcus pneumoniae. The authors illustrate how benefits and risks of drug treatment can be weighed quantitatively in decision-based risk functions and subsequently used in the estimation of drug dosing.

  • 32. Välitalo, Pyry
    et al.
    Kumpulainen, Elina
    Manner, Minna
    Kokki, Merja
    Lehtonen, Marko
    Hooker, Andrew C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ranta, Veli-Pekka
    Kokki, Hannu
    Plasma and Cerebrospinal Fluid Pharmacokinetics of Naproxen in Children2012In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, no 10, p. 1516-1526Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to characterize pediatric pharmacokinetics and central nervous system exposure of naproxen after oral administration. The pharmacokinetics of naproxen was studied in 53 healthy children aged 3 months to 12 years undergoing surgery with spinal anesthesia. Children received preoperatively a single dose of 10 mg/kg oral naproxen suspension. A single cerebrospinal fluid (CSF) sample (n = 52) was collected at the induction of anesthesia, and plasma samples (n = 270) were collected before, during, and after the operation (up to 51 hours after administration). A population pharmacokinetic model was built using the NONMEM software. Naproxen concentrations in plasma were well described by a 2-compartment model. The estimated oral clearance (CL/F) was 0.62 L/h when linearly scaled by weight to 70 kg. The apparent volume of distribution at steady state (Vss/F) was 12.5 L/70 kg. The findings are consistent with previously reported pharmacokinetic parameters for children older than 5 years. Naproxen permeated into the CSF and reached CSF concentrations that were 4 times higher than unbound plasma concentrations. Based on these data, weight can be used as a basis for naproxen dosing in children older than 3 months of age.

  • 33. Østerberg, Ole
    et al.
    Savic, Radojka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nørgaard, Jens Peter
    Vande Walle, Johan
    Agersø, Henrik
    Pharmacokinetics of Desmopressin Administrated as an Oral Lyophilisate Dosage Form in Children With Primary Nocturnal Enuresis and Healthy Adults2006In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 46, no 10, p. 1204-1211Article in journal (Refereed)
    Abstract [en]

    The population pharmacokinetics of desmopressin in children with nocturnal enuresis and in healthy adults were compared using a 1-compartment model with first-order absorption and first-order elimination. In addition, the model consisted of a number of transit compartments before absorption to describe a lag-time. The model gave an adequate description of adult as well as children data and provided a statistically significant better fit to data than a standard lag-time model. The main difference in the pharmacokinetics between children and adults was the absorption delay. The pharmacokinetic difference was minor and presumably of no clinical relevance.

1 - 33 of 33
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