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Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function: evidence of interconversion
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
2008 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, no 6, 855-863 p.Article in journal (Refereed) Published
Abstract [en]

AIMS

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

METHODS

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

RESULTS

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

CONCLUSION

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

Place, publisher, year, edition, pages
2008. Vol. 65, no 6, 855-863 p.
Keyword [en]
acyl glucuronide, interconversion, mechanistic modelling, NONMEM, population pharmacokinetics, tesaglitazar
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97051DOI: 10.1111/j.1365-2125.2008.03110.xISI: 000255751300008OAI: oai:DiVA.org:uu-97051DiVA: diva2:171832
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2011-10-06Bibliographically approved
In thesis
1. Safety and Efficacy Modelling in Anti-Diabetic Drug Development
Open this publication in new window or tab >>Safety and Efficacy Modelling in Anti-Diabetic Drug Development
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A central aim in drug development is to ensure that the new drug is efficacious and safe in the intended patient population.

Mathematical models describing the pharmacokinetic-pharmacodynamic (PK-PD) properties of a drug are valuable to increase the knowledge about drug effects and disease and can be used to inform decisions. The aim of this thesis was to develop mechanism-based PK-PD-disease models for important safety and efficacy biomarkers used in anti-diabetic drug development.

Population PK, PK-PD and disease models were developed, based on data from clinical studies in subjects with varying degrees of renal function, non-diabetic subjects with insulin resistance and patients with type 2 diabetes mellitus (T2DM), receiving a peroxisome proliferator-activated receptor (PPAR) α/γ agonist, tesaglitazar.

The PK model showed that a decreased renal elimination of the metabolite in renally impaired subjects leads to increased levels of metabolite undergoing interconversion and subsequent accumulation of tesaglitazar. Tesaglitazar negatively affects the glomerular filtration rate (GFR), and since renal function affects tesaglitazar exposure, a PK-PD model was developed to simultaneously describe this interrelationship. The model and data showed that all patients had decreases in GFR, which were reversible when discontinuing treatment.

The PK-PD model described the interplay between fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and haemoglobin in T2DM patients. It provided a mechanistically plausible description of the release and aging of red blood cells (RBC), and the glucose dependent glycosylation of RBC to HbA1c. The PK-PD model for FPG and fasting insulin, incorporating components for β-cell mass, insulin sensitivity and impact of disease and drug treatment, realistically described the complex glucose homeostasis in the heterogeneous patient population.

The mechanism-based PK, PK-PD and disease models increase the understanding about T2DM and important biomarkers, and can be used to improve decision making in the development of future anti-diabetic drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 71
Keyword
Pharmaceutical biosciences, pharmacokinetic, pharmacodynamic, mechanism-based, modelling, type 2 diabetes mellitus, tesaglitazar, PPAR, drug development, NONMEM, Farmaceutisk biovetenskap
Identifiers
urn:nbn:se:uu:diva-8648 (URN)978-91-554-7164-4 (ISBN)
Public defence
2008-05-09, B21, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2010-12-09Bibliographically approved

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Karlsson, Mats O.

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