15th Conference on Retroviruses and Opportunistic Infections Boston, Massachusetts - February 3-6, 2008

Conf Retrovir Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 47LB)

Deborah hirt¹, S Urien¹, E Rey², D Ekouevi³, S Blanche⁴, G gray⁵, P Coffie³, K Leang Sim⁶, F Dabis⁷, and J M Treluyer ^1
1Hosp Cochin, Univ Paris Descartes, France; ²Hosp Cochin, France; ³Prgm PACCI, Abidjan, Côte d`Ivoire; ⁴Univ Paris Descartes, France; ⁵Univ of the Witwatersrand, Soweto, South Africa; ⁶Hosp Calmette, Phnom Penh, Cambodia; and ⁷INSERM U593, Inst for Publ Hlth, Epi and Devt, Univ Victor Segalen, Bordeaux, France

BACKGROUND: Tenofovir, the active part of tenofovir disoproxil fumarate (TDF) is a potent nucleoside reverse transcriptase inhibitor used in adult treatment for HIV infection but not in pregnant woman for the prevention of HIV mother-to-child transmission. The aim was to evaluate tenofovir pharmacokinetics in pregnant women and in their neonates and to suggest the optimal prophylactic dose for neonates in their first day of life.

METHODS: We administered to 38 HIV-1-infected pregnant women 2 tablets of TDF (300 mg)/emtricitabine (FTC) (200 mg) at the initiation of labor and 1 tablet of TDF/FTC daily for 7 days postpartum. By pair, 11 maternal, 1 cord blood, and 2 neonatal tenofovir plasma concentrations were measured using an high performance liquid chromatography (HPLC) published method. A population pharmacokinetic model was developed to describe tenofovir concentration time-courses and estimate inter-patient variability in mothers and neonates. The optimal neonatal tenofovir dosage should produce the same AUC as observed in adults and should allow to have concentrations as long as possible over adult minimal concentrations.

RESULTS: Data were best described by a 2-compartment model with first order absorption and elimination for mothers. An effect compartment linked to maternal circulation for cord bloods and after delivery a neonatal compartment disconnected, with a distribution volume proportional to the maternal one, on a bodyweight base. Mean estimates (inter-patient variability) were: for the mother, k_a 0.51 h^-1 (67%), CL/F 51.3 L.h^-1 (30%), V₁/F 343 L, Q/F 143 L.h^-1 (39%), and V₂/F 1490L, for the cord k_1e 0.27 h^-1, and k_e1 0.45 h^-1. Absorption was faster and greater for women with caesarian section than with vaginal delivery. After a 600-mg TDF administration, median population tenofovir AUC, C_max, and C_min in pregnant women were 2.73 mg.L^-1.h, 0.31 and 0.056 mg/L, respectively. At delivery, maternal and cord median tenofovir concentrations were respectively 0.13 and 0.10 mg.L^-1. Neonatal plasma half-life was 8.3 hours (45%), suggesting low neonatal concentrations quickly after birth.

CONCLUSIONS: TDF 600 mg before delivery produces similar concentrations to those of HIV infected people taking 300 mg daily. If time elapsed between maternal administration and delivery is >12 hours, 2 tablets of TDF/FTC should be re-administered. Tenofovir was shown to have good placental transfer. Administering 13 mg/kg of TDF as soon as possible after birth should produce neonatal concentrations comparable to those observed in adults.

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2008-02-03
47LB

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