In the present work, mother and child FTC pharmacokinetics were satisfactorily described by the proposed compartmental model. The following observations support the validity of this model.
Population-predicted maternal, cord blood, and neonatal concentrations were well correlated with observed concentrations. The population model was validated, thanks to the visual predictive check method.
In pregnant women, the AUC obtained from our population model was decreased (i.e., 14.3 mg/liter·h for a 400-mg dose and 7.15 mg/liter·h for a 200-mg dose) compared to that for nonpregnant adults (10.7 mg/liter·h for a 200-mg dose). This is in agreement with the PATCG/IMPAACT P1026 study which reports, during the third trimester of pregnancy, a median AUC of 8.6 mg/liter·h for a 200-mg dose (3
As shown in Table , despite a higher elimination clearance in pregnant women than in nonpregnant adults, the 400-mg FTC administration before delivery produces higher exposure than does the 200-mg administration in other adults at steady state. Calculating FTC clearance as a dose-to-AUC ratio, we found 28.0 liters/h for pregnant women (our study), compared to 18.7 liters/h (4
) and 20.4 liters/h for other adults (15
). FTC clearance was increased by 37 or 50%. FTC is primarily excreted by the kidney by both glomerular filtration and tubular secretion, with 86% recovery of the dose achieved in urine, as described in the full prescribing information for Truvada (http://www.gilead.com/pdf/truvada_pi.pdf
). During pregnancy, renal plasma flow increases by 25 to 50% and glomerular filtration rate by 50%, which should have enhanced FTC elimination (13
). The lowest FTC clearance increase in the PATCG/IMPAACT P1026 study (23.3 liters/h versus 28.0 liters/h in our study) may be due the sampling time during pregnancy (third trimester versus the day of delivery in our study). None of the covariates tested had an effect on maternal absorption or elimination clearance.
No data were reported on FTC placental transfer. In this study, from one sample at delivery (at various times after drug administration) in each mother-cord blood pair, we could draw maternal and cord blood concentration curves as a function of the delay and estimate intersubject and residual variabilities. Placental transfer was estimated as fetal- to maternal-exposure ratio to the drug. We found a relatively constant ratio of 80% for a delivery occurring at least 4 h after maternal drug administration. This transfer seems to be due mainly to a passive diffusion of the drug through the placenta. Data about active transport are missing.
Cord blood concentrations were relatively high (0.72 mg/liter) compared to the adult minimal concentrations previously reported (0.07 mg/liter). This was due to both a good placental transfer of the drug and a higher exposure in mothers; with 400 mg of FTC at delivery time, maternal exposure was higher than the exposure with 200 mg in nonpregnant adults. So, even if women delivered a long time after drug intake, cord blood concentrations should remain over the adult minimal concentration. However, readministering two tablets of Truvada to the mother after 12 h of labor (if she did not deliver yet, as suggested for tenofovir [unpublished data]) would produce reasonable cord blood FTC concentrations (similar to cord blood concentrations of neonates born 5 h after first maternal drug intake).
The FTC median neonatal half-life was 10.6 h, in agreement with the Blum et al. study reporting half-lives of 12.5 h in neonates from birth to 21 days, 11.5 h for 22- to 42-day-old infants, and 11.8 h for 43- to 90-day-old children (5
). Moreover, these half-lives are comparable to those for children (9.3 to 11.7 h for 2- to 17-year-old children) (17
) and adults (10.5 h in the Blum et al. study, 9.4 h in the Zhong et al. study, and 8.3 h in the Ramanathan et al. study) (4
Since the model was validated, thanks to the visual predictive check method, it was used to simulate the optimal dosage. For this, it was assumed that the child had the same absorption rate and bioavailability as the mother and that its volume of distribution was proportional to the total maternal volume distribution on a BW basis. Accordingly, in our model, the mean volume of distribution was 16.9 liters for a child weighing 2.7 kg at birth, which is close to the volume of distribution of 14 liters (t1/2
= 12.5 h and CL = 13 ml/min) found in the 18 children from days 0 to 21 of the Blum et al. study (5
). Moreover, even with a 100% error in the neonatal volume of distribution, the AUC0→24 h
and the time during which the concentration was >0.077 mg/liter showed a <20% change. The optimal single neonatal dose was determined in order to obtain an exposure in neonates similar to the known exposure in adults (i.e., 10.4 mg/liter·h) and concentrations above the residual adult concentration (0.077 mg/liter) before and as long as possible after neonatal administration. Criteria were based on plasma FTC concentrations, although intracellular FTC triphosphate concentrations would have been more appropriate to follow the pharmacologically active part of FTC. It was also supposed that the enzymes of phosphorylation were matured in the neonates (16
). For practical reasons, we suggest that FTC should be administered to the neonate at the same time as tenofovir (unpublished data). As previously shown, tenofovir should be administered quickly after birth, i.e., 1 hour after delivery, so we simulated concentrations obtained with 1, 2, or 3 mg FTC/kg given 1 hour after birth to the neonate. A 2-mg/kg FTC administration given 12 h after birth was also simulated. Taking into account the high exposure of the fetus to the drug due to maternal administration (AUC0→24 h
= 8.2 mg/liter·h), only 1 mg FTC/kg was needed 1 hour after birth to reach an AUC0→24 h
of 10.1 mg/liter·h. However, if the neonate could only be administered FTC 12 h after birth, the dose would increase to 2 mg/kg. This dosage is recommended for a single administration following birth and not for repeated doses as in the Blum et al. study (5
In conclusion, the maternal 400-mg FTC administration before delivery produces higher exposure than does the 200-mg administration in other adults at steady state. FTC placental transfer, described by the neonatal- to maternal-exposure ratio, was around 80%. Finally, neonates should receive 1 mg FTC/kg as soon as possible after birth or 2 mg/kg 12 h after birth to have concentrations comparable to those observed in adults. The second step of the TEmAA trial will validate these recommendations.