1. ¹Department of Medical Science, Clinical Pharmacology, AstraZeneca R&D Mölndal, Mölndal, Sweden
2. ²Department of Biopharmaceutical Sciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden
3. ³Clinical Cardiovascular, AstraZeneca R&D Wilmington, Wilmington, Delaware, USA
4. ⁴Department of Medical Science, Clinical Pharmacology, AstraZeneca R&D Wilmington, Wilmington, Delaware, USA

Correspondence: B Hamrén, (bengt.hamren@astrazeneca.com)

Received 31 October 2007; Accepted 2 January 2008; Published online 19 March 2008.

Abstract

Pharmacokinetic (PK) pharmacodynamic (PD) modeling was applied to understand and quantitate the interplay between tesaglitazar (a peroxisome proliferator–activated receptor / 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 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.