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

Direct link
Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
2008 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6519, Vol. 84, no 2, 228-235 p.Article in journal (Refereed) Published
Abstract [en]

Pharmacokinetic (PK) pharmacodynamic (PD) modeling was applied to understand and quantitate the interplay between tesaglitazar (a peroxisome proliferator-activated receptor alpha/gamma agonist) exposure, fasting plasma glucose (FPG), hemoglobin (Hb), and glycosylated hemoglobin (HbA1c) in type 2 diabetic patients. Data originated from a 12-week dose-ranging study with tesaglitazar. The primary objective was to develop a mechanism-based PD model for the FPG-HbA1c relationship. The secondary objective was to investigate possible mechanisms for the tesaglitazar effect on Hb. Following initiation of tesaglitazar therapy, time to new FPG steady state was similar to 9 weeks, and tesaglitazar potency in females was twice that in males. The model included aging of red blood cells (RBCs) using a transit compartment approach. The RBC life span was estimated to 135 days. The transformation from RBC to HbA1c was modeled as an FPG-dependent process. The model indicated that the tesaglitazar effect on Hb was caused by hemodilution of RBCs.

Place, publisher, year, edition, pages
2008. Vol. 84, no 2, 228-235 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97053DOI: 10.1038/clpt.2008.2ISI: 000258445200019OAI: oai:DiVA.org:uu-97053DiVA: diva2:171834
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2011-10-07Bibliographically 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
Division of Pharmacokinetics and Drug Therapy
In the same journal
Clinical Pharmacology and Therapeutics
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 247 hits
ReferencesLink to record
Permanent link

Direct link