Population pharmacokinetic modelling of pimozide and its relation to CYP2D6 genotype.
Gianluca Nucci, Keith Muir and Roberto Gomeni
Clinical Pharmacokinetics Modelling & Simulation, GlaxoSmithKline, Verona Italy
Background: Pimozide is a dopamine receptor antagonist used to treat obsessive compulsive disorder associated with Tourette's syndrome. In humans, pimozide is believed to be primarily metabolised by cytochrome P450 enzyme system CYP3A4 [1, 2] although CYP2D6 may also play a role .
Objectives: The objectives of the population pharmacokinetic analysis were to model the pharmacokinetics of pimozide in subjects of different CYP2D6 phenotypes in order to elucidate the role of CYP2D6 in pimozide disposition.
Methods: A two-compartment model with first-order absorption, and lag-time was implemented for Pimozide as basic model. It was fitted to the data of 32 healthy volunteers using NONMEM. Individual covariate used to refine the model estimates were age, weight, sex and CYP2D6 polymorphisms.
Results: Based on CYP2D6 genotype, the subjects had the following predicted metabolizer status: Extensive (EM) N=26, Intermediate (IM) N=4, and Poor (PM) N=2. CYP2D6 genotype was found to highly significantly improve model fitting to the data, with average population clearance of 14, 36 and 55 L/h in PM, IM and EM respectively. The variability of pimozide plasma concentrations was caused to a relevant degree by CYP2D6 (CVb% is decreased from 60% to 30% when CYP2D6 activity was taken into consideration). Individual body weight was found to be significantly linked to pimozide volume of distribution.
Conclusions: These population PK results suggest that pimozide CYP2D6 metaboliser status impacts significantly on the PK of pimozide, and CYP2D6 is at least as important as CYP3A4 in pimozide metabolism.
References:
[1] Desta Z, Kerbusch T, Flockhart DA. Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6).Clin Pharmacol Ther. 65(1):10-20, 1999.
[2] Desta Z, Kerbusch T, Soukhova N, Richard E, Ko JW, Flockhart DA. Identification and characterization of human cytochrome P450 isoforms interacting with pimozide. J Pharmacol Exp Ther. 285(2):428-37, 1998.
[3] Richard E, Soukova N, & Kerbusch T: Metabolism of pimozide by CYP3A and CYP2D6 in human liver microsomes Clin Pharmacol Ther. 61(2):232, 1997
