Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates

Abstract

The objectives of this study were to evaluate emtricitabine (FTC) pharmacokinetics in pregnant women and their neonates and to determine the optimal prophylactic dose for neonates after birth to prevent mother-to-child transmission of human immunodeficiency virus (HIV). A total of 38 HIV-infected pregnant women were administered tenofovir disoproxyl fumarate (300 mg)-FTC (200 mg) tablets-two tablets at the initiation of labor and one daily for 7 days postpartum. By pair, 11 maternal, one cord blood, and two neonatal FTC concentrations were measured using a high-performance liquid chromatography-tandem mass spectrometry validated method and analyzed by a population approach. Model and mean estimates (interpatient variability) were a two-compartment model for mothers, with an absorption rate constant of 0.54 h(-1) (61%), apparent elimination and intercompartmental clearances of 23.2 (17%) and 6.04 liters x h(-1), and apparent central and peripheral volumes of 127 and 237 liters, respectively; an effect compartment linked to maternal circulation for cord blood and a neonatal compartment disconnected, after delivery, with a 10.6-h half-life (30%). After the 400-mg FTC administration, the median population area under the concentration-time curve and the minimal and maximal plasma FTC concentrations in pregnant women were 14.3 mg x liter(-1) x h and 1.68 and 0.076 mg/liter, respectively. At delivery, median (range) predicted maternal and cord blood FTC concentrations were, respectively, 1.16 (0.14 to 1.99) and 0.72 (0.05 to 1.19) mg x liter(-1). We concluded that the 400-mg FTC administration in pregnant women produces higher exposition than does the 200-mg administration in other adults, at steady state. FTC was shown to have good placental transfer (80%). Administering 1 mg FTC/kg as soon as possible after birth or 2 mg/kg 12 h after birth should produce neonatal concentrations comparable to the concentrations observed in adults.

Figures

FIG. 1.

Population pharmacokinetic model for the simultaneous prediction of FTC concentrations in the mother, the cord blood (top), and the neonate (bottom). A two-compartment model with first-order absorption and elimination best described maternal data. For cord blood FTC 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 own elimination. F denotes bioavailability, D the maternal FTC dose, ka the absorption rate constant, CL the maternal elimination clearance from the central compartment, V1 the volume of the central maternal compartment, Q2 the maternal intercompartmental clearance, V2 the volume of the peripheral maternal compartment, k1F the mother-to-fetus transfer rate constant, kF1 the fetus-to-mother transfer rate constant, kF0 neonate elimination rate constant, VF the neonate volume of distribution, BWM the maternal BW, and BWF the neonatal BW.

FIG. 2.

(Left) Observed (○) and population-predicted (line) maternal FTC concentrations versus time. (Right) Observed (○) and population-predicted (lines) FTC concentrations in cord blood (top) and neonatal plasma (bottom) versus time.

FIG. 3.

Evaluation of the final model. Comparison between the 5th (lower dashed line), 50th (full line), and 95th (upper dashed line) percentiles obtained from 1,000 simulations and the observed data (○) for FTC concentrations in mother (left panel), cord blood (middle panel), and neonate (right panel).

FIG. 4.

(Top) Population-predicted FTC concentrations in the mother (full line) and her neonate (dashed line) (cord blood equation before delivery and neonatal equation after) versus time for 2-h (left panel), 6-h (middle panel), or 12-h (right panel) delays between drug administration and delivery time. (Bottom) Neonatal to maternal FTC AUC ratio as a function of the delay between drug administration and delivery time.