Physiologically-Based Pharmacokinetic (PBPK) Modeling of the CYP2C8 Substrate Pioglitazone
Denise Tuerk (1), Nina Hanke (1) and Thorsten Lehr (1)
(1) Clinical Pharmacy, Saarland University, Saarbruecken, Germany
Objectives: Pioglitazone, a thiazolidinedione, is indicated to treat type II diabetes mellitus. It is an agonist of the nuclear transcription factor peroxisome-proliferator-activated receptor γ and modifies gene-expression, resulting in an insulin sensitizing effect [1]. Pioglitazone is predominantly metabolized by CYP2C8 [2] and it is recommended by the U.S. Food and Drug Administration as a moderate sensitive CYP2C8 substrate [3]. Co-administration of pioglitazone with the strong CYP2C8 inhibitor gemfibrozil leads to a 3.4-fold increase in the area under the curve (AUC) of pioglitazone [4]. Our objective was to establish a PBPK model of the victim drug pioglitazone.
Methods: A PBPK model of pioglitazone was built in PK-Sim® (Version 6.3.2) [5]. Drug-dependent parameters (e.g. acid dissociation constant, solubility) and concentration-time profiles of 11 clinical studies (oral dosing from 15 to 45 mg daily, single- and multiple-dosing) were obtained from literature. Parameters for which no information was found were optimized to describe an internal data set (5 studies) of observed concentration-time profiles. The PBPK model was evaluated by prediction of an external data set (6 studies).
Results: The final pioglitazone model includes metabolism by CYP2C8, CYP3A4 [2] and glomerular filtration. Furthermore, the model is able to describe the effects of a CYP2C8 polymorphism on pioglitazone plasma concentrations. The CYP2C8*3/*3 genotype is related to an increase in pioglitazone metabolism compared to wild-type (CYP2C8*1/*1) and leads to a decrease in the AUC by 34% [6]. The external data set is well predicted. The quality of the model can be characterized by AUC ratios (AUC predicted /AUC observed), which show a very low geometric mean fold absolute deviation of 1.09 (range 1.00-1.28, n=11).
Conclusions: We successfully established a PBPK model of pioglitazone as a CYP2C8 victim drug. The model can be applied to predict drug-gene interactions and to evaluate the drug-drug interaction potential of drugs which are CYP2C8 inhibitors or inducers, to help with clinical study design, drug approval and labeling questions.
References:
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