The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir.

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.

As a result of high inter-patient variability, and efficacy-concentration and toxicity-concentration relationships, optimization of HIV-protease inhibitor (PI) doses based on plasma concentrations could be beneficial. During a 48-week open prospective non-randomized interventional study of 115 protease inhibitor-naïve patients initiating an indinavir/ritonavir- or lopinavir/ritonavir-, or nelfinavir-containing therapy, protease inhibitor dose was modified when plasma trough concentrations (C(trough)) at weeks 2, 8, 16 and 24 were outside predefined optimal concentration ranges. Failure of the strategy was defined as the proportions of patients with HIV-RNA above 200 copies/mL from weeks 24 to 48 and/or experiencing grades 2, 3 or 4 PI-related adverse events during the study; proportion of patients with last C(trough) measurement outside the concentration range was determined at each visit. Virological failure and/or occurrence of adverse event were observed in 37/94 assessable patients (39%; 95% CI: 29.4-50.0). In the on-treatment analysis, failure of the strategy was noted in 16% of indinavir/r- or lopinavir/r-treated patients (8/51; 95% CI: 7.0-28.6; virological failure: 2; adverse event: 6) but in 44% of nelfinavir-treated patients (11/25; 95% CI: 24.4-65.1; virological failure: 10; adverse event: 1); C(trough) concentrations outside the range were less frequent at the last measurement than at W2 (41% vs. 66%; P < 0.05), with proportions of 35% for indinavir/r- or lopinavir/r-treated patients, but 57% for nelfinavir-treated patients. The proposed strategy of therapeutic drug monitoring may be beneficial to indinavir/r- and lopinavir/r-treated patients, but failed to move concentrations into the predefined range and to produce the expected virological success for nelfinavir-treated patients.