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


CONCLUSIONS
* 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.


OBJECTIVE
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-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.


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 C(mean) 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.
Hirt
Déborah
D
Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Saint-Vincent-de-Paul, Université Paris - Descartes, Paris, France. deborah.hirt@univ-paris5.fr
Mentré
France
F
Tran
Agnès
A
Rey
Elisabeth
E
Auleley
Solange
S
Salmon
Dominique
D
Duval
Xavier
X
Tréluyer
Jean-Marc
JM
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000235:genetics*; D001711:Biotransformation / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000235:genetics*; D019888:Nelfinavir / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic; D016896:Treatment Outcome; D019562:Viral Load / Q000706:statistics & numerical data
D017320:HIV Protease Inhibitors; C517960:M8-nelfinavir; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019888:Nelfinavir