Effect of CYP2C19 polymorphism on nelfinavir to M8 biotransformation in HIV patients

Abstract

Aims: To evaluate the effect of CYP2C19 polymorphism on nelfinavir and M8 pharmacokinetic variability in human immunodeficiency virus-infected patients and to study the link between pharmacokinetic exposure and short-term efficacy and toxicity. Methods: Nelfinavir (n = 120) and M8 (n = 119) concentrations were measured in 34 protease inhibitor-naïve patients. Two weeks after initiating the treatment, blood samples were taken before, 1, 3 and 6 h after drug administration. Genotyping for CYP3A4, 3A5, 2C19 and MDR1 was performed. A population pharmacokinetic model was developed to describe nelfinavir-M8 concentration time-courses and to estimate interpatient variability. The influence of individual characteristics and genotypes were tested using a likelihood ratio test. Estimated mean (Cmean), maximal (C max) and trough (Ctrough) nelfinavir and M8 concentrations were correlated to short-term virological efficacy and tolerance using Spearman nonparametric correlation tests. Results: A one-compartment model with first-order absorption, elimination and metabolism to M8 best described nelfinavir data. M8 was modelled by an additional compartment. Mean pharmacokinetic estimates and the corresponding intersubject variabilities were: absorption rate 0.17 h-1 (99%), absorption lag time 0.82 h, apparent nelfinavir total clearance 52 l h-1 (49%), apparent nelfinavir volume of distribution 191 l, M8 elimination rate constant 1.76 h-1 and nelfinavir to M8 0.39 h-1 (59%) in *1/*1 patients and 0.20 h-1 in *1/*2 or *2/*2 patients for CYP2C19*2. Nelfinavir Cmean was positively correlated to glycaemia and triglyceride increases (P = 0.02 and P = 0.04, respectively). Conclusions: The rate of metabolism of nelfinavir to M8 was reduced by 50% in patients with *1/*2 or *2/*2 genotype for CYP2C19 compared with those with *1/*1 genotype. © 2007 The Authors.