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

* Nelfinavir is an HIV protease inhibitor, substrate of the transporter P-glycoprotein and metabolized via CYP2C19, CYP3A4 and CYP3A5 enzymes. * Pharmacokinetic studies have shown wide interindividual variability of nelfinavir concentrations, some of this variability perhaps caused by variant drug metabolism or transporter genes. * For CYP3A4*1B and CYP3A5*3 polymorphism, results from three studies are in agreement, showing no difference in nelfinavir concentrations between patients with these different genotypes. * However, for MDR1 and CYP2C19 polymorphism, there have been contradictory studies, showing either no impact on nelfinavir concentration or modified concentrations which could influence virological response.

* Patients with an *1/*2 or *2/*2 genotype for CYP2C19 had a nelfinavir to M8 biotransformation divided by 2 compared with *1/*1 patients. * No evidence of any influence of MDR1 polymorphism on nelfinavir absorption could be detected.

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.

Nelfinavir (n = 120) and M8 (n = 119) concentrations were measured in 34 protease inhibitor-naive 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 (C(mean)), maximal (C(max)) and trough (C(trough)) nelfinavir and M8 concentrations were correlated to short-term virological efficacy and tolerance using Spearman nonparametric correlation tests.

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 C(mean) was positively correlated to glycaemia and triglyceride increases (P = 0.02 and P = 0.04, respectively).

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.