Plasma and Intracellular Tenofovir Pharmacokinetics in the Neonate (ANRS 12109 Trial, Step 2)

Abstract

The objective of this study was to investigate for the first time tenofovir (TFV) pharmacokinetics in plasma and peripheral blood mononuclear cells (PBMCs) of the neonate. HIV-1-infected pregnant women received two tablets of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) at onset of labor and then one tablet daily for 7 days postpartum. A single dose of 13 mg/kg of body weight of TDF was administered to 36 neonates within 12 h of life after the HIV-1-infected mothers had been administered two tablets of TDF-emtricitabine at delivery. A total of 626 samples collected within the 2 days after the drug administration were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed by a population approach. In the neonate, the median TFV plasma area under the curve and minimal and maximal concentrations, respectively, were 3.73 mg/liter ⅐ h and 0.076 and 0.29 mg/liter. In PBMCs, TFV concentrations were detectable in all fetuses, whereas tenofovir diphosphate (TFV-DP) was quantifiable in only two fetuses, suggesting a lag in appearance of TFV-DP. The median TFV-DP neonatal concentration was 146 fmol/10 6 cells (interquartile range [IQR], 53 to 430 fmol/10 6 cells); two neonates had very high TFV-DP concentrations (1,530 and 2963 fmol/10 6 cells). The 13-mg/kg TDF dose given to neonates produced plasma TFV and intracellular active TFV-DP concentrations similar to those in adults. This dose should be given immediately after birth to reduce the delay before the active compound TFV-DP appears in cells.The combination tenofovir (TFV) disoproxil fumarate (TDF)-emtricitabine (FTC) has been considered during the perinatal period to prevent mother-to-child transmission (PMTCT) and/or to reduce viral resistance to nevirapine (NVP) (3, 8); its administration to pregnant women at the onset of labor followed by a single dose to the neonate was thus proposed. The TEmAA (Tenofovir/Emtricitabine in Africa and Asia) ANRS 12109 Trial study was an open, phase I/II trial built in two steps. In the first step, the TDF-FTC combination was administered to HIV-infected pregnant women, and the pharmacokinetics, safety, and toxicity were evaluated for mothers and their newborns (2). After estimation of the maternal and fetal FTC-tenofovir (TFV) pharmacokinetic profiles, the mother was proposed to renew the dose after 12 h if she had not delivered yet in order to maintain effective TFV fetal concentrations. Then, a 13-mg/kg of body weight TDF dose (at birth) was proposed for neonates to obtain similar exposure to that in adults (16). In the second step of the TEmAA study, the TDF-FTC combination was administered to HIV-infected pregnant women and to their newborns, allowing evaluation of these dose propositions based on the results obtained in the first step of the study. Tolerance and virological results have been reported elsewhere (24).TFV, like other nucleoside analogues, undergoes intracellular phosphorylation by various cellular kinases to an active diphosphate (TFV-DP), which competiti...

Pharmacokinetics and Safety of Single-Dose Tenofovir Disoproxil Fumarate and Emtricitabine in HIV-1-Infected Pregnant Women and Their Infants

“…A very surprising finding in our study, corroborated by others, is the very rapid decline in infant TFV concentrations immediately after birth (14,16,23). Infant rhesus monkeys demonstrate a 65% decrease in the clearance of TFV, which is thought to be due to immature renal function and which suggests that TFV elimination would also be decreased in neonates (37).…”

“…Although TFV crossed the placenta well in our subjects, with a CB/M TFV concentration ratio of 0.73, 4 of 10 infants in group 1 and 5 of 15 infants in groups 2 and 3 failed to exceed the target concentration of 50 ng/ml in cord blood. In previous studies of intrapartum administration of nevirapine and tenofovir, the time between maternal dosing and delivery played an important role in determining fetal exposure to a maternally administered drug (14,16,22 Pharmacokinetic findings from repeat dosing in two women have demonstrated concentrations comparable to those in women who had received a single dose as well as no significant safety issues (16,34).…”

“…This also suggests that despite low plasma concentrations following oral administration of TDF, substantial intracellular concentrations of the active metabolite TFV-DP may be present. TFV-DP was assessed by Hirt et al in 20 cord blood specimens following maternal intrapartum dosing of 600 mg and in 22 infants 10 to 45 h old following a dose of 13 mg/kg of TDF suspension (16). Only 2 of the cord blood specimens had quantifiable TFV-DP present, but the infant concentrations were comparable to those in adults at steady state.…”

“…Hirt et al had proposed an infant dose of 13 mg/kg based on a simulation of data from maternal intrapartum TDF doses and the washout of transplacentally acquired drugs from infants (14). They have recently reported their findings using a population PK approach (16). The median infant TFV AUCs and C max were approximately twice those seen with our 4-mg/kg dose (3,730 versus 1,841 ng ⅐ h/ml and 290 versus 101 ng/ml, respectively).…”

11.0 References

“…In addition, double-dose tenofovir has been shown to cross the placenta rapidly to preload the infant and should be considered where the prematurity is such that the infant is likely to have difficulty taking PEP in the first few days of life [139]. 5.4.6 Women presenting in labour/ROM/requiring delivery without a documented HIV result must be recommended to have an urgent HIV test.…”