Very high concentrations of active intracellular phosphorylated emtricitabine in neonates (ANRS 12109 trial, step 2)

Our objective was to investigate neonatal emtricitabine (FTC) plasma and intracellular pharmacokinetics. The study was designed as a phase I/II prospective trial in two sequential steps evaluating the combination of tenofovir disoproxil fumarate (TDF) and FTC for the prevention of mother-to-child-transmission (PMTCT) of HIV. HIV-1-infected pregnant women received two tablets of TDF (300 mg) and FTC (200 mg) at onset of labor and then one tablet daily for 7 days postpartum. Based on the data obtained in the first part of the Tenofovir/Emtricitabine in Africa and Asia (TEmAA) Study, single doses of 2 mg/kg of FTC and 13 mg/kg of TDF were given to the neonates within 12 h after birth. A total of 540 FTC plasma concentrations and 44 active intracellular phosphorylated metabolite FTC-TP concentrations were taken from the 36 enrolled women and their neonates. Concentrations were measured by the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and analyzed by a population approach. The proposed dose obtained by simulations based on plasma drug concentrations was confirmed. However, median FTC-TP exposures were, respectively, 5.9 and 6.8 times higher in the fetus and the neonate than in the adult. High FTC-TP concentrations were observed in the four children who had serious adverse events (SAEs), but the link between FTC-TP concentrations and SAEs in children was not formally identified. The exposure to the active form of FTC was high in neonates despite plasma drug concentrations equivalent to those in adults. Our results are similar to those obtained with zidovudine or lamivudine.