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

Abstract

What is already known about this subject • 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. What this study adds • 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. 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 (Cmax) 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.

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

“…A recent study found that patients (n=166) on escitalopram therapy, carrying the CYP2C19*17 allele (UM phenotype) exhibited 42 % lower plasma concentrations than those homozygous for CYP2C19*1 and underlined the necessity of dose adjustment (123). The rate of nelfi navir (for HIV treatment) biotransformation to M8 was reduced by 50 % in patients with the CYP2C19*1/*2 or *2/*2 genotype compared to those with the *1/*1 genotype, with consequences of modifi ed short-term effi cacy and toxicity and fi nal virological response (124). Some reports documented that the CYP2C19*2 loss-of-function polymorphism was associated with an increased treatment-related mortality (TRM) in patients undergoing allogenic transplantation (125).…”

Functional Genetic Polymorphisms inCYP2C19Gene in Relation to Cardiac Side Effects and Treatment Dose in a Methadone Maintenance Cohort

“…We have considered the possible effects of co-occurrence of HIV infection in the MMT patients in this study because several HIV medications are known to inhibit the enzymatic activities of CYP2C19 and 3A4 (Burger et al, 2006;Hirt et al, 2008), thus would affect the metabolism of methadone (Ward et al, 2003). In fact, only three subjects in the present cohort had been treated with HIV medications.…”

Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

“…Since AZT and 3TC are orally administered, the k a of AZT, the Tk0 of 3TC, CL/F, and V/F were identifiable. Concerning metabolites, since no urinary concentrations were available, only the parameters (CL m /F)/k m and (V m /F)/k m were identifiable (21,29). We could thus determine k em as the ratio of both previous parameters and also the half-lives of the parent drugs and metabolites.…”

“…Patients received a combination of two NRTIs plus one PI as antiretroviral therapy. Population PK analyses of the data from the nelfinavir group and the ritonavir-boosted indinavir group obtained in this trial were performed to evaluate the impact of genetic polymorphisms on nelfinavir and indinavir pharmaco-kinetics (PK) and the link between concentrations and shortterm efficacy (10,21). A substudy of the COPHAR2-ANRS111 trial consisted of measuring plasma and intracellular concentrations of AZT and 3TC in patients whose treatment contained AZT and 3TC as NRTIs with a PI.…”