Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates.
The aim of the present study was to describe the nevirapine (NVP) pharmacokinetics (PK) in pregnant women and their neonates and to evaluate the transplacental drug transfer and administration scheme for the prevention of mother-to-child transmission. Thirty-eight HIV-1-infected pregnant women were administered one tablet of NVP (200 mg) and two tablets of tenofovir-emtricitabine (Truvada) at the initiation of labor. Children were given NVP syrup (2 mg/kg of body weight) as a single dose (sdNVP) on the first day of life. By pair, NVP concentrations were measured in 11 maternal, 1 cord blood, and 2 neonatal plasma samples and analyzed by a population approach. A one-compartment model was used for mothers and neonates; the absorption rate constants for mothers and neonates were 0.95 h(-1) (intersubject variability, 111%) and 0.39 h(-1), respectively; the apparent elimination clearances were 1.42 liter·h(-1) (intersubject variability, 22%) and 0.035 liter·h(-1), respectively; and apparent volumes of distribution were 87.3 liters (intersubject variability, 25%) and 5.65 liters, respectively. An effect compartment was linked to maternal circulation by mother-to-cord and cord-to-mother rate constants of 1.10 h(-1) and 1.43 h(-1), respectively. Placental transfer, expressed as the fetal-to-maternal area under the curve ratio, was 75%. Neonates had a very long half-lives (110 h) compared to adults. In the 38 mothers, the simulated median individual predicted time during which the NVP concentration remained above the half-maximal inhibitory concentration (IC(50)) was 13.2 days (range, 12 to 19.2 days). Thus, the administration of tenofovir-emtricitabine for at least 3 weeks after delivery should be considered to prevent the emergence of resistant viruses. The neonate must receive sdNVP immediately after birth when the infant is born less than 30 min after maternal drug intake to keep NVP concentrations above the IC(50).
Benaboud
Sihem
S
EA3620, Université Paris-Descartes, Paris, France.
Ekouévi
Didier K
DK
Urien
Saik
S
Rey
Elisabeth
E
Arrivé
Elise
E
Blanche
Stéphane
S
Gray
Glenda
G
Sim
Kruy Leang
KL
Avit
Divine
D
McIntyre
James
J
Nerrienet
Eric
E
Dabis
François
F
Tréluyer
Jean-Marc
JM
Hirt
Déborah
D
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007231:Infant, Newborn; D019829:Nevirapine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D063065:Organophosphonates / Q000627:therapeutic use; D011247:Pregnancy; D000068698:Tenofovir; D016896:Treatment Outcome; D055815:Young Adult; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; D063065:Organophosphonates; D003841:Deoxycytidine; D015215:Zidovudine; D019829:Nevirapine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine