Pharmacokinetic modelling of the placental transfer of nelfinavir and its M8 metabolite: a population study using 75 maternal-cord plasma samples.
OBJECTIVE
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.
Hirt
Déborah
D
Pharmacologie Clinique, Assistance publique- Hôpitaux de Paris, groupe hospitalier Cochin-Saint-Vincent-de-Paul, Faculté de médecine René Descartes, Université Paris 5, Paris, France. deborah.hirt@univ-paris5.fr
Urien
Saïk
S
Jullien
Vincent
V
Firtion
Ghislaine
G
Chappuy
Hélène
H
Rey
Elisabeth
E
Pons
Gérard
G
Mandelbrot
Laurent
L
Treluyer
Jean-Marc
JM
D000653:Amniotic Fluid / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D019888:Nelfinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy; D016896:Treatment Outcome
D017320:HIV Protease Inhibitors; D019888:Nelfinavir