A pooled population pharmacokinetic analysis of tesaglitazar in patients with type 2 diabetes or with manifestations of insulin resistance

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Objectives: Tesaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) 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 of this analysis was to characterize the pharmacokinetics of tesaglitazar in the target patient populations.

Methods: Pharmacokinetic data were pooled from SH-SBT-0001 (SIR), 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 insulin resistance (IR), and from SH-SBD-0001 (GLAD), a 12-week, randomised, double-blind, placebo-controlled study of tesaglitazar (0.1, 0.5, 1.0, 2.0 or 3.0 mg once daily) in patients with type 2 diabetes. Pharmacokinetic data from 582 patients (2470 observations in total) were included. Covariates evaluated in the analysis were renal function (assessed as calculated creatinine clearance (CrCL) using lean body mass as a measure of body weight), gender, age, body weight, smoking status, patient population and serum-albumin. Non-linear mixed-effects modelling, using NONMEM, was used for the analysis.

Results: The pharmacokinetics of tesaglitazar were well described by a one-compartment model with first order absorption and elimination. The mean oral clearance (CL/F) was found to be positively correlated to renal function, and was 0.12 L/h for a individual with a CrCL of 76 mL/min. The overall between-patient variability in CL/F was 37 %, and decreased to 28 % when differences in renal function were accounted for.  The mean oral volume of distribution (Vz/F) and half-life was 10.7 L and 61 h, respectively. The area under the concentration time curve, dose normalised to 1 mg, was approximately 20 µmol h/L. None of the other covariates tested was found to affect CL/F when renal function was accounted for. No covariates were found to influence Vz/F.

Conclusion: The pharmacokinetics of tesaglitazar in patients with manifestations of IR or type 2 diabetes were well characterised by population modelling, and the results were in agreement with those previously reported in healthy subjects.