Congenital CMV Infection: Determination of Transplacental Passage of Aciclovir by Ex Vivo Placental Perfusion.

Abstract

To quantify the transplacental transfer of aciclovir at an amount equivalent to 2 g of valaciclovir corresponding to the fractionated dosing regimen given four times daily used to reduce congenital cytomegalovirus (CMV) transmission and to treat the CMV-infected fetus. Experimental ex vivo study. Dual closed-loop perfusion of isolated human placental cotyledons. Placentas collected at term. Placental transfer was assessed using the dual closed-loop ex vivo perfusion. Aciclovir was perfused in the maternal compartment at a concentration corresponding to the oral dose of 2 g of valaciclovir taken every 6 h (8 g/day). Samples from maternal and fetal compartments were collected at regular intervals over a 3-h period. Aciclovir concentrations were measured using chromatographic techniques. The transfer rate was calculated as the ratio of the number of moles of fetal aciclovir to the number of fetal and maternal moles at 3 h. Nine perfusion experiments met the criteria for success and could be used for interpretation. The mean transplacental transfer rate of aciclovir was 17.4% (SD: 7.8%). With a single 2 g dose, fetal exposure to aciclovir remained below the IC50 for CMV. The transplacental transfer of aciclovir is low. Despite aciclovir's low molecular weight and hydrophilicity, moderate plasma protein binding and rapid renal elimination may limit placental availability, and the observed transfer was lower than expected for passive diffusion, suggesting involvement of facilitated uptake or efflux mechanisms. These results support the current rationale for high-dose valaciclovir regimens in pregnancy and suggest a potential role for transporter-mediated drug transfer.