Modélisation d'un cycle entéro-hépatique chez l'homme par approche pharmacocinétique de population

PARIS-BIUP (751062107) / SudocSudocFranceF

Méthodes d'analyses pharmacocinétique dans le développement clinique

PARIS-BIUP (751062107) / SudocSudocFranceF

Pharmacocinétique de population du nelfinavir

Le nelfinavir est un inhibiteur de protéase utilisé dans le traitement du SIDA. Ce médicament est métabolisé par le CYP2C19 en un métabolite actif, le M8. Il existe une grande variabilité interindividuelle des concentrations plasmatiques de nelfinavir et de M8 avec des conséquences pour l efficacité thérapeutique. Dans quatre publications différentes, nous avons analysé les facteurs de variabilité de ces concentrations grâce à une méthode de pharmacocinétique de population : chez la femme enceinte et au cours de l accouchement, chez l enfant et le fœtus et chez les sujets présentant un polymorphisme génétique pour le CYP2C19. Puis à partir des estimations des paramètres pharmacocinétiques individuelles, nous avons calculé la dose nécessaire pour atteindre une concentration efficace. Lorsque nous disposions de mesures d efficacité et de toxicité, des relations pharmacocinétique pharmacodynamique ont été étudiées. Ces résultats ont permis des recommandations posologiques adaptées.Nelfinavir is a protease inhibitor used for AIDS treatment. This drug is metabolized by CYP2C19 to an active metabolite, M8. There is a high interindividual variability in nelfinavir and M8 plasma concentrations, with consequences on therapeutic efficacy. In four different publications, we analyzed variability factors of these concentrations thanks to population pharmacokinetics method: in pregnant women and women at delivery, in children and fetus and in adults with genetic polymorphism for the CYP2C19. Then, from the estimated individual pharmacokinetic parameters, we calculated minimal dose necessary to reach an effective concentration. When data concerning efficacy and toxicity were available, pharmacokinetic pharmacodynamic relationships were studied. The results obtained permitted to give adapted doses recommendations.PARIS-BIUP (751062107) / SudocSudocFranceF

Pharmacokinetics and Virological Efficacy after Switch to Once-Daily Lopinavir-Ritonavir in Treatment-Experienced HIV-1-Infected Children▿

Lopinavir-ritonavir (LPV/r) is a protease inhibitor that is used twice daily (BID) in the treatment of HIV infection in children. In the context of a single-center observational study, a switch to a once-a-day (QD) LPV/r regimen was proposed for considerations of convenience and to support adherence. The aims of this study were to compare the pharmacokinetics, viral loads, percentages of CD4+ T cells, and lipid profiles after switching from a twice-daily to a once-daily regimen of LPV/r in experienced children. For this purpose, LPV concentrations, viral loads, CD4+ T cells, and biochemistry data were measured in routine therapeutic drug monitoring procedures in 45 children and adolescents. Thirty-six children were switched to the QD regimen. Nine children on the BID or QD regimen were added for pharmacokinetic-study purposes only. The QD trough concentrations (Ctrough) of lopinavir in plasma were significantly lower than those observed with the BID regimen (P < 0.0001), but the 24-h exposure levels were not significantly lower with the QD than with the BID regimen (P = 0.09). Among 34 evaluable patients who switched from the BID to the QD regimen, the virological efficacy of LPV/r appeared to differ (P < 0.001), with 74% and 57% of viral loads, respectively, being <50 copies/ml (mean follow-up times, 33 and 20 months). Among 22 patients with stable virological control before the switch, 12 experienced either failure or blip (one observation of detectable viral load between two observations of undetectable viral load) after the switch. The change from the BID to the QD regimen did not result in significant differences in CD4+ T cell percentages or total cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels. The switch from the BID to the QD LPV/r regimen led to equivalent exposure and lower Ctrough values and resulted in lower levels of virological control in these antiretroviral-experienced children

Age-Related Effects on Nelfinavir and M8 Pharmacokinetics: a Population Study with 182 Children

As a relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established, nelfinavir pharmacokinetics was investigated in order to optimize the individual treatment schedule in a pediatric population. A population pharmacokinetic model was developed to describe the concentration-time course of nelfinavir and its active metabolite M8. Individual characteristics were used to explain the large interindividual variability in children. Data from therapeutic drug monitoring in 182 children treated with nelfinavir were analyzed with NONMEM. Then Food and Drug Administration (FDA) current recommendations were evaluated estimating the percentage of children who reached the target minimum plasma concentration (0.8 mg/liter) by using Bayesian estimates. Nelfinavir pharmacokinetics was described by a one- compartment model with linear absorption and elimination. Pharmacokinetic estimates and the corresponding intersubject variabilities for the model were as follows: nelfinavir total clearance, 0.93 liters/h/kg (39%); volume of distribution, 6.9 liters/kg (109%); absorption rate, 0.5 h(−1); formation clearance fraction to hydroxy-tert-butylamide (M8), 0.025; M8 elimination rate, 1.88 h(−1) (49%). Apparent nelfinavir total clearance and volume of distribution decreased as a function of age. M8 elimination rate was increased by concomitant administration of nevirapine or efavirenz. Our data confirm that the FDA recommendations for children from 2 to 13 years are optimal and that the dose recommended for children younger than 2 years is adequate for the children from 2 months to 2 years old. However, in children younger than 2 months, the proposed nelfinavir newborn dose of 40 mg/kg of body weight twice daily is inadequate and we suggest increasing the dose to 50 to 60 mg/kg administered thrice daily. This assumption should be further evaluated

Pregnancy-Related Effects on Nelfinavir-M8 Pharmacokinetics: a Population Study with 133 Women

A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h(−1); absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL(10)/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL(1M)/F), 0.65 liters/h (69%); and M8 elimination rate constant (k(M0)), 3.3 h(−1) (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h(−1)) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery

Pharmacokinetic modelling of the placental transfer of nelfinavir and its M8 metabolite: a population study using 75 maternal-cord plasma samples

What is already known about this subjectNelfinavir is an HIV protease inhibitor used in pregnant women, although no ex vivo and few in vivo data are available describing its transfer across the placenta.What this study addsA population pharmacokinetic study was performed on maternal, cord plasma and amniotic fluid samples to characterize the concentration–time courses of nelfinavir and its metabolite M8 in the three compartments and to study the influence of covariates, such as weight and duration of pregnancy, on placental transfer.The pharmacokinetics of nelfinavir and M8 were satisfactorily described by a three compartment model. The median nelfinavir fetus : maternal concentration ratio was 25% for maternal concentrations between 0.1 and 2.5 mg l−1, between the 31st and 41st week of gestation, irrespective of bodyweight. This ratio was significantly higher for M8 (a 55% increase).To our knowledge this is the first population pharmacokinetic integrated model to describe satisfactorily the maternal-foetal-amniotic fluid transfer of a drug

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

International audienceWHAT 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-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