A population PK-PD model for effects of Sipoglitazar on FPG and HbA1c in patients with type II diabetes.
Fran Stringer (1), Joost DeJongh (2), Graham Scott (3) and Meindert Danhof (4)
(1) Clinical Pharmacology Dept, Takeda Pharmaceutical Company, Osaka, Japan; (2) LAP&P Consultants BV, Leiden, The Netherlands; (3) Clinical Pharmacology, Takeda Global Research & Development Centre Ltd. Europe, London, United Kingdom; (4) Leiden-Amsterdam Centre for Drug Research, Division of Pharmacology, Leiden, The Netherlands
Objectives: Sipoglitazar is a PPAR γ, α & δ agonist for treating type 2 diabetes mellitus (T2DM) by improving insulin sensitivity. Sipoglitazar undergoes phase II biotransformation by conjugation catalyzed by UGT. UGT2B15 genotype is a covariate for clearance in individual patients as was reported previously from a population PK analysis[1]. The present population PK-PD analysis was performed to study the role of PK in differences of drug effects in sipoglitazar on both fasting plasma glucose (FPG) and HbA1c observed between the different UGT2B15 genotypes (UGT2B15*1/*1, UGT2B15*1/*2, and UGT2B15*2/*2).
Methods: Efficacy and safety of sipoglitazar compared to placebo were assessed in T2DM patients in two Phase II randomized, double-blind studies (sipoglitazar QD: 8, 16, 32 or 64 mg; sipoglitazar BID: 16 or 32 mg; placebo). All patients were treatment naïve and received lifestyle and dietary counseling prior to and during the study. Drug intake started after a 7-10 day run-in for a total period of 13 weeks. PK and PD data for FPG and HbA1c were collected throughout the trial. The individual PK parameters derived from a previous analysis were used to calculate individual exposure. Changes in FPG and HbA1c levels over time were described as a function of individual drug exposure using a simultaneous, cascading indirect response model structure.
Results: The effects on FPG and HbA1c could successfully be described for placebo and sipoglitazar treated groups in all three UGT2B15 genotypes. Differences in drug effects between genotypes were fully explained by differences in drug exposure. Maximum reduction of FPG (Emax) due to sipoglitazar exposure was approximately 50% for the typical patient. In addition, a small but significant reduction of HbA1c was observed independent of FPG reduction, in placebo and sipoglitazar treated subjects.
Conclusions: The current PK-PD analysis confirms that UGT2B15 genotype is a major determinant for differences in FPG and HbA1c response to sipoglitazar treatment between diabetes patients, due to related differences in drug exposure. Part of the reduction in HbA1c levels was independent of the drug effects on FPG and a dedicated model parameter could be identified for this process.
References:
[1] Stringer F, Ploeger BA, DeJongh J, Scott G, Urquhart R, Karim A, Danhof M. Evaluation of the Impact of UGT Polymorphism on the Pharmacokinetics and Pharmacodynamics of the Novel PPAR Agonist Sipoglitazar. J Clin Pharmacol. 2013 Mar;53(3):256-63.