uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Pharmacokinetic-Pharmacodynamic Assessment of the Interrelationships Between Tesaglitazar Exposure and Renal Function in Patients With Type 2 Diabetes Mellitus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2012 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, no 9, 1317-1327 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2012. Vol. 52, no 9, 1317-1327 p.
Keyword [en]
Tesaglitazar, peroxisome proliferator–activated receptor (PPAR), renal function, pharmacokinetics-pharmacodynamics (PK-PD)
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97052DOI: 10.1177/0091270011416937ISI: 000308227400004OAI: oai:DiVA.org:uu-97052DiVA: diva2:171833
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2012-10-05Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 71
Pharmaceutical biosciences, pharmacokinetic, pharmacodynamic, mechanism-based, modelling, type 2 diabetes mellitus, tesaglitazar, PPAR, drug development, NONMEM, Farmaceutisk biovetenskap
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
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2010-12-09Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Karlsson, Mats O.
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Journal of clinical pharmacology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 233 hits
ReferencesLink to record
Permanent link

Direct link