Mechanism-based pharmacokinetic and pharmacodynamic modelling of tesaglitazar in type 2 diabetes patients
Hamrén, Bengt(1), Elisabeth Björk (1), Mats O. Karlsson (2)
(1) AstraZeneca R&D Mölndal, S-43183 Mölndal, Sweden. (2) Division of Pharmacokinetics and Drug Therapy, Faculty of Pharmacy, Uppsala University, S 75124 Uppsala, Sweden
Objectives: Tesaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist in development for the treatment of glucose and lipid abnormalities in patients with type 2 diabetes (T2D). We developed a pharmacokinetic (PK) and pharmacodynamic (PD) model of the interplay between tesaglitazar exposure, fasting plasma glucose (FPG), haemoglobin (Hb) and glycosylated Hb (HbA1c) over time for patients with T2D.
Methods: PK and PD data were collected from GLAD (Glucose and Lipid Assessment in Diabetes), a 12-week, randomized, double-blind, placebo-controlled study of tesaglitazar (0.1, 0.5, 1.0, 2.0 or 3.0 mg) once daily in patients with T2D. Covariates evaluated were prior anti-diabetic therapy, gender, age, body weight and renal function. Non-linear mixed-effects modelling using NONMEM evaluated tesaglitazar PK and characterized the relationship between tesaglitazar exposure and effects on FPG using an indirect response model with a stimulatory drug effect on FPG elimination. A mechanism-based PD model was developed to describe the time course and interaction between FPG, Hb and HbA1c during treatment. This model included release of red blood cells (RBC, monitored as Hb) into the circulation and ageing of Hb in the blood. HbA1c lifespan was described in parallel to Hb, where HbA1c was formed as a function of FPG.
Results: Tesaglitazar PK were well described by a one-compartment model with first order elimination. Mean oral clearance was positively correlated with renal function but was not affected by other covariates after accounting for renal function. No covariates influenced other PK parameters. Patients with prior anti-diabetic therapy had a greater placebo response than naïve patients. The time to PD steady state was ~10 wks and mean maximal reduction in FPG was 66%. As expected from observations with PPARγ agonists, a gender difference in EC50 was observed. None of the other covariates affected PD. The lifespan of Hb (and HbA1c) was estimated as 136 days. A power function described FPG and Hb interactions and this estimate was in agreement with the literature. Gender had a minor impact on RBC release.
Conclusions: This mechanism-based PK/PD model could qualitatively and quantitatively describe PD interactions between FPG, Hb and HbA1c during tesaglitazar treatment in patients with T2D.