Population Pharmacokinetics of Emtricitabine in HIV-1 infected Pregnant Women and their neonates ( ANRS 12109 )

1 Objectives: To evaluate emtricitabine (FTC) pharmacokinetics (PK) in pregnant women and 2 their neonates and to determine the optimal prophylactic dose for neonates after birth to 3 prevent mother-to-child transmission of HIV (PMTCT). 4 Methods: 38 HIV-infected pregnant women were administered Tenofovir Disoproxyl 5 Fumarate (TDF, 300mg)emtricitabine (FTC, 200mg) tablets: 2 at the initiation of labour and 6 1 daily for 7 days postpartum. By pair, 11 maternal, 1 cord blood and 2 neonatal FTC 7 concentrations were measured using an HPLC MS MS validated method and analyzed by a 8 population approach. 9 Results: Model and mean estimates (inter-patient variability) were a 2-compartment model for 10 mother with absorption rate constant 0.54 h (61%), apparent elimination and 11 intercompartmental clearance 23.2 (17%) and 6.04 L.h and apparent central and peripheral 12 volume 127 and 237L; an effect compartment linked to maternal circulation for cord and a 13 neonatal compartment disconnected, after delivery, with a 10.6 hours half life (30%). After 14 the 400 mg FTC administration, median population AUC, Cmax and Cmin in pregnant women 15 were 14.3 mg.L.h, 1.68 and 0.076 mg/L respectively. At delivery, median (range) FTC 16 predicted maternal and cord concentrations were respectively 1.16 (0.14–1.99) and 0.72 17 (0.05–1.19) mg.L. 18 Conclusion: The 400 mg FTC administration in pregnant women produces higher exposition 19 than the 200 mg administration to adults, at steady state. FTC was shown to have good 20 placental transfer (80%). Administering FTC 1 mg/kg as soon as possible after birth or 2 21 mg/kg 12 hours after birth should produce neonatal concentrations comparable to those 22 observed in adults. 23 Introduction 24 To prevent mother-to-child transmission of HIV around the delivery, a single-dose 25 administration of nevirapine (sdNVP) administered at start of labour is the most common 26 antiretroviral regimen used in resource-limited settings, as recommended by the World Health 27 Organization in the antiretroviral drugs for treating pregnant women and preventing HIV 28 infection in infants report (http://www.who.int/hiv/pub/guidelines/pmtctguidelines3.pdf). 29 However, the use of sdNVP results in resistance mutations in 15 to 70% of women, at 4 to 6 30 weeks postpartum, compromising the success of subsequent treatments with NVP in mother 31 and child (7, 9). A recent clinical study suggests that adding a single dose of TDF and FTC at 32 delivery may reduce those resistances by half (6). 33 Emtricitabine is a potent, once daily (QD) nucleoside reverse transcriptase inhibitor approved 34 for the treatment of human immunodeficiency virus (HIV) in adults and children older than 3 35 months in combination with other antiretroviral agents. The physiological changes associated 36 with pregnancy can lead to significant variations in pharmacokinetics (10, 12, 14). However, 37 few pharmacokinetic data on emtricitabine in pregnant women (3) and no data on placental 38 transfer are available. Only one study reports pharmacokinetic of emtricitabine in neonates 39 exposed to HIV in utero; apparent elimination clearance was 13 mL/min in 5 to 21 days-old 40 neonates and 22 mL/min in 23 to 42 days-old neonates (5). This suggests that the youngest 41 neonates have the lowest elimination clearance. The neonatal pharmacokinetics just after birth 42 is still unknown. 43 In the present work, a population pharmacokinetic study was performed on mother, cord and 44 neonatal plasma samples in order i) to describe the concentration-time courses of FTC in 45 mothers, the transfer of FTC from maternal plasma to cord plasma and the neonatal 46 elimination, ii) to study the influence of covariates (such maternal bodyweight, gestational 47 age, type of delivery, maternal creatinine, neonatal bodyweight, height and body surface area) 48 on FTC pharmacokinetics and iii) to model various dosing strategies to determine optimal 49 dosing scheme for newborn. 50