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.
Hirt
Déborah
D
Pharmacologie Clinique, Hôpital Saint Vincent de Paul, Paris, France. deborah.hirt@univ-paris5.fr
Treluyer
Jean-Marc
JM
Jullien
Vincent
V
Firtion
Ghislaine
G
Chappuy
Hélène
H
Rey
Elisabeth
E
Pons
Gérard
G
Mandelbrot
Laurent
L
Urien
Saïk
S
D000328:Adult; D001499:Bayes Theorem; D036861:Delivery, Obstetric; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D015233:Models, Statistical; D019888:Nelfinavir / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D011247:Pregnancy; D012189:Retrospective Studies
D017320:HIV Protease Inhibitors; D019888:Nelfinavir