Lack of Placental Transfer of Enfuvirtide in an ex vivo Human Placental Cotyledon Perfusion Model
Claudia Ferreira*1,2, Claudia Ferreira*1,2, P Ceccaldi1,3, P Ceccaldi1,3, B Visseaux4, L Gavard1,3, L Gavard1,3, G Peytavin4, S Gil5, L Mandelbrot1,3, and L Mandelbrot1,3
1Hosp Louis Mourier, Colombes, France; 2French Natl Agency for Res on AIDS and Viral Hepatitis; 3Univ Paris 7, France; 4Hosp Bichat-Claude Bernard, Paris, France; and 5UPRES EA 2706, Univ of Pharma Sci, Chatenay-Malabry, France
Background: Enfuvirtide (T20), a 36-amino acid peptide
inhibitor of HIV-1 host cell membrane fusion, is the first of a new class of ART
agents, the entry inhibitors. T20 is mainly used as a component of rescue
treatment in multi-experienced HIV-infected patients because of no clinically
significant interaction with concomitantly given drugs metabolized by CYP450
enzymes. The purpose of this study was to
determine the maternal-fetal-placental transfer of T20 using an ex vivo human placental cotyledon perfusion
Methods: Placentas obtained from uncomplicated
full-term pregnancies were collected immediately after delivery. We perfused 3
isolated cotyledons according to the modified method described by Schneider et
al, with human serum albumin (2 g/L) in Earles perfusate. Maternal perfusion
comprised antipyrine 20 mg/L as internal control and T20 (90 mg/1250 mL).
Antipyrine and T20 concentrations were determined by high-performance liquid
chromatography (HPLC) coupled with spectrofluorimetry or ultraviolet detection
with limit of quantitation of 50 ng/mL. Fetal transfer rate (ratio
of fetal to maternal concentrations) and clearance index (ratio of T20 to
antipyrine fetal transfer rate) were calculated.
Results: In all 3 validated experiments, T20 was below the
limit of quantitation in the fetal compartment.
Concentrations measured in the maternal compartment were significantly
above Cmax (5.0 1.7 mg/L) with a mean of 12.4 mg/L (6.5 to 16.2
mg/L). Mean antipyrine fetal transfer rate was 36% (22 to 45%).
Conclusions: Even at maternal concentrations twice above
therapeutic levels, no transplacental passage of T20 was observed in the ex vivo human placental perfusion model.
The high molecular weight and high protein binding of T20 (4492 kDa) may
account for the lack of placental transfer. This result suggests that T-20
could be used in HIV-infected pregnant women without causing fetal exposure.