Article date: April 2008
By: Déborah Hirt, France Mentré, Agnès Tran, Elisabeth Rey, Solange Auleley, Dominique Salmon, Xavier Duval, Jean‐Marc Tréluyer, The COPHAR2‐ ANRS Study Group in Volume 65, Issue 4, pages 548-557
What is already known about this subject
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.
DOI: 10.1111/j.1365-2125.2007.03039.x
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