Very High Concentrations of Active Intracellular Phosphorylated Emtricitabine in Neonates (ANRS 12109 Trial, Step 2)

Abstract

The tenofovir-emtricitabine (FTC) combination was proposed during the perinatal period for prevention of motherto-child transmission (PMTCT) of HIV and/or to reduce viral resistance to nevirapine, thanks to administration to pregnant women at the start of labor (2, 5). In a previous study using a population pharmacokinetic approach, we proposed the following doses and schemes for the use of FTC during the perinatal period: for the mother, two tablets of tenofovir disoproxil fumarate (TDF) (300 mg)-FTC (200 mg) were given at the onset of labor, and if she did not deliver within the 12 h from the first administration, another two tablets of TDF-FTC, followed by one tablet per day were administered for 7 days postpartum. For the neonate, a 2-mg/kg FTC single dose within the 12 h after birth was proposed; this recommendation was based on pharmacokinetics data obtained from neonates from the transplacental transfer of FTC, after administration of FTC to the pregnant women before delivery (9). It was coadministered with a single dose of 13 mg/kg of TDF.The first objective of the following study was to evaluate our selected dose of FTC in pregnant women and their neonates. The second objective was to measure the active intracellular metabolites of FTC in neonates, as previously high intracellular phosphorylated metabolites for lamivudine triphosphate (3TC-TP) and zidovudine triphosphate (AZT-TP) during the first 2 weeks of life have been detected (7).

Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients

“…As the data did not allow us to estimate an absorption rate constant, a model with a k a equal to the slope of the distribution phase or models with fixed k a values were tested. The k a value estimated in our population (0.53 h Ϫ1 ) thanks to the model developed (i.e., with k a ϭ ␣) was close to previously published values for pregnant women (0.54 h Ϫ1 and 0.709 h Ϫ1 ) (10,11). However, even by fixing k a to these values, the best fit was obtained for the model with a common value estimated for k a and ␣.…”

“…1), we could not estimate the absorption rate constant (k a ). Models with fixed k a values (10,11) were tested. However, these k a values have only been estimated in pregnant women.…”

Protecting the Fetus Against HIV Infection: A Systematic Review of Placental Transfer of Antiretrovirals

“…The second article on this emtricitabine population pharmacokinetic study reported on the active, phosphorylated intracellular form of emtricitabine. It measured this metabolite in cord blood from 36 deliveries using liquid chromatography-tandem mass spectrometry and compared with literature that described concentrations of this metabolite in non-pregnant adults [78]. From this study the median predicted exposure to the active intracellular phosphorylated emtricitabine was 5.9 times higher in the cord blood than in adults [78] despite the lower exposure to the parent drug reported in the first part of the study [77].…”

“…It measured this metabolite in cord blood from 36 deliveries using liquid chromatography-tandem mass spectrometry and compared with literature that described concentrations of this metabolite in non-pregnant adults [78]. From this study the median predicted exposure to the active intracellular phosphorylated emtricitabine was 5.9 times higher in the cord blood than in adults [78] despite the lower exposure to the parent drug reported in the first part of the study [77]. This is relevant clinically since it implies that measurement of the parent drug may underestimate the extent of placental transfer of active drug and hence measurement of the active form in future studies may provide more meaningful results.…”

Plasma Tenofovir, Emtricitabine, and Rilpivirine and Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate Pharmacokinetics following Drug Intake Cessation

“…Modeling of plasma tenofovir and emtricitabine linked to their IC anabolites (TFV-DP and FTC-TP) using various approaches has been previously described (9)(10)(11). This methodology was explored to allow prediction of TFV-DP and FTC-TP concentrations, up to 168 h (7 days) following drug cessation, from plasma data.…”