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- Title
Pharmacokinetic modelling of the placental transfer of nelfinavir and its M8 metabolite: a population study using 75 maternal-cord plasma samples.
- Authors
Hirt, Déborah; Urien, Saïk; Jullien, Vincent; Firtion, Ghislaine; Chappuy, Hélène; Rey, Elisabeth; Pons, Gérard; Mandelbrot, Laurent; Treluyer, Jean-Marc
- Abstract
What is already known about this subject • Nelfinavir 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 adds • A 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. Aims A population pharmacokinetic model was developed to characterize the transfer of nelfinavir and its active metabolite M8 from maternal to cord plasma and amniotic fluid. Methods Concentration data were obtained from 75 women on the day of delivery and for whom maternal, umbilical plasma and amniotic fluid samples were collected. Data from 53 pregnant, 61 nonpregnant and seven consecutively pregnant and non pregnant women were then added to the database, the contents of which were analyzed using NONMEM. Results Nelfinavir and M8 concentrations in maternal plasma, umbilical plasma and amniotic fluid were described by six connected compartments. Mean (% intersubject variability) population estimates were: absorption rate 00.67 h−1, lag time 00.87 h, oral clearance and volume of distribution: 39.5 l h−1 (53%), and 557 l for non pregnant and pregnant women, respectively, and 115 l h−1 (132%) and 1626 l, respectively, on the day of delivery, M8 formation clearance 0.77 l h−1 and M8 elimination rate constant 03.41 h−1 (74%). For nelfinavir and M8, respectively, the mother-to-cord parameters were 0.058 l h−1 (34%), and 00.35 h−1 (76%), the cord-to-amniotic fluid rate constants were 0.23 and 00.59 h−1, and the elimination rate constants from amniotic fluid were 0.36 and 00.49 h−1. The nelfinavir fetus : maternal concentration ratio was 25% for maternal concentrations between 0.1 and 2.5 mg l−1, between the 31 and 41st week of gestation. Conclusions The low transfer of nelfinavir from the placenta is unlikely to protect the fetus from vertical HIV-1 transmission.
- Subjects
PHARMACOKINETICS; ANTIRETROVIRAL agents; THERAPEUTIC use of protease inhibitors; HIV infections; THERAPEUTICS; HIV-positive women; PREGNANT women
- Publication
British Journal of Clinical Pharmacology, 2007, Vol 64, Issue 5, p634
- ISSN
0306-5251
- Publication type
Article
- DOI
10.1111/j.1365-2125.2007.02885.x