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Clinical Trial
. 2011 Jan;55(1):331-7.
doi: 10.1128/AAC.00631-10. Epub 2010 Oct 18.

Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates

Sihem Benaboud  1 , Didier K Ekouévi, Saik Urien, Elisabeth Rey, Elise Arrivé, Stéphane Blanche, Glenda Gray, Kruy Leang Sim, Divine Avit, James McIntyre, Eric Nerrienet, François Dabis, Jean-Marc Tréluyer, Déborah Hirt; TEmAA ANRS 12109 Study Group
Collaborators, Affiliations
Clinical Trial

Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates

Sihem Benaboud et al. Antimicrob Agents Chemother. 2011 Jan.

Abstract

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).

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Figures

FIG. 1.
FIG. 1.
Population pharmacokinetic model for the simultaneous prediction of nevirapine concentrations in the mother, the cord (fetus; top), and the neonate (bottom). A one-compartment model with first-order absorption and elimination best described maternal data. For cord concentrations, an effect compartment is modeled as a virtual compartment linked to the maternal plasma compartment by a first-order process. After delivery, the fetal compartment is disconnected and the neonate has his or her own absorption and elimination.
FIG. 2.
FIG. 2.
Observed (○) and model-predicted (lines) nevirapine concentrations versus time in mothers (left), cord (umbilical) blood (upper right), and neonates (bottom right).
FIG. 3.
FIG. 3.
Evaluation of the final model: comparison of the 5th (dashed line), 50th (solid line), and 95th (dashed line) percentiles obtained from 1,000 simulations and the observed data (○) for nevirapine concentrations in mother (left), cord blood (middle), and neonate (right).
FIG. 4.
FIG. 4.
Simulated concentration-time courses for maternal plasma (semilog scale). Solid vertical lines, shortest and longest delays during which NVP concentrations remain above the IC50 limit (dashed line).
FIG. 5.
FIG. 5.
Simulated concentration-time courses of NVP in neonates before dosing for different delays between the time of maternal intake and delivery: (i) 30 min, (ii) 2 h, (iii) 5 h, and (iv) 8 h. Horizontal solid lines, IC50; horizontal dashed line, 10 times the IC50.
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