Pharmacokinetic and pharmacodynamic modelling of the dual PPAR α/γ agonist tesaglitazar in patients with manifestations of insulin resistance

Objective: Tesaglitazar is a novel, dual peroxisome proliferator-activated receptor α/γ agonist under clinical development for the treatment of glucose and lipid abnormalities in patients with type 2 diabetes and metabolic syndrome. The aim was to characterize the pharmacokinetics (PK) of tesaglitazar and its pharmacodynamic (PD) effect on fasting serum-triglycerides (TG) in patients with manifestations of insulin resistance (IR).

Materials and methods: PK and TG data were collected from the Study in Insulin Resistance (SIR: SH-SBT-0001), a 12-week, randomised, double-blind, placebo-controlled study of tesaglitazar (0.1, 0.25, 0.5 or 1.0 mg once daily) in non-diabetic patients with manifestations of IR. In total, 389 patients were included in the analysis, and PK data were collected from 240 patients. Fasting TG was collected at 10 visits, and all observations were used in the analysis. Covariates evaluated were renal function, gender, age and body weight. Non-linear mixed-effects modelling, using NONMEM, was employed, first to describe the PK of tesaglitazar, and secondly to characterise the relationship between exposure of tesaglitazar and its effect on TG.

Results: The pharmacokinetics of tesaglitazar was well described by a one-compartment model with first order elimination. The mean oral clearance (CL/F) was found to be positively correlated to renal function, and was 0.13 L/h for an individual having a CrCL of 90 mL/min. The overall between patient variability in CL/F was 30 %, and decreased to 24 % when differences in renal function were accounted for.  The mean oral volume of distribution (Vz/F) and half-life were 11.6 L and 63 h, respectively. None of the other covariates tested were found to affect CL/F when renal function was accounted for. No covariates influenced the other PK parameters. The relationship between exposure of tesaglitazar and change in TG was modelled with an indirect response model.  The mean baseline TG was 2.8 mmol/L. The time to PD steady state was approximately 16 days and the mean maximal reduction in TG was 67%. The between patient variability in EC50 decreased from 77% to 76% when including gender as a covariate in the model. The estimated EC50 values were 0.76 and 0.38 µmol/L for males and females respectively. None of the other covariates affected the PD parameters.

Conclusions: The pharmacokinetic/pharmacodynamic relationship of tesaglitazar was well characterised by population PK/PD modelling.  This model provides an accurate description of the pharmacodynamic effect on triglycerides of tesaglitazar in patients with manifestation of IR.