Effect of CYP2C19 polymorphism on nelfinavir to M8 biotransformation in HIV patients.
D. Hirt, F. Mentré, A. Tran, E. Rey, S. Auleley, X. Duval, D. Salmon, J.M. Tréluyer, and the COPHAR2- ANRS study group.
Hôpital Cochin-Saint Vincent de Paul
Objectives: To evaluate the effect of CYP2C19 polymorphism on nelfinavir and M8 pharmacokinetic variability in HIV infected patients and to study the link between pharmacokinetic exposure and short term efficacy and toxicity.
Methods: One hundred and twenty nelfinavir and 119 M8 concentrations were measured in 34 naive-patients enrolled in the COPHAR 2-ANRS 111 trial. Two weeks after initiating the treatment, 4 blood samples were taken 1, 3, 6 and 12 hours after drug administration. Genotyping for CYP3A4, 3A5, 2C19 and MDR1 (exon 21 and 26) was performed. A population pharmacokinetic model was developed in order to describe nelfinavir and M8 concentration time-courses and estimate inter-patient variabilities. The influence of individual characteristics and genotypes were tested in the population model using a likelihood ratio test. Maximum, minimum and mean individual concentrations derived from the estimated individual parameters were linked to short-term efficacy and toxicity 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 inter-subject variabilities (%) were: absorption rate 0.17 h-1(99%), absorption lag time 0.82 h, apparent nelfinavir clearance 52 L/h (49%), apparent nelfinavir volume of distribution 191 L, M8 elimination rate constant 1.76 h-1 and the parameter expressing nelfinavir to M8 transformation that could be estimated (CLm/Vm) 0.39 h-1 (59%). This parameter CLm/Vm was divided by 1.98 in AG or AA patients for CYP2C19*2 compared to GG patients. With respect to link between pharmacokinetic and short term metabolic toxicity, nelfinavir minimum plasma concentrations and mean concentrations were positively correlated to increase of glycemia (p=0.03, p=0.02). Mean concentrations was also positively correlated with triglycerides increase (p=0.04).
Conclusions: CYP2C19*2 polymorphism influences nelfinavir - M8 pharmacokinetics.