Bidirectional transfer of pritelivir across term human placenta and its effect on placental functions

Genital herpes in pregnancy is treated with nucleoside analog drugs such as acyclovir to reduce the risk of mother-to-neonate transfer of the virus. Pritelivir is a novel anti-herpes simplex virus drug that is effective against acyclovir-resistant viral strains and is currently in phase 3 clinical trial for nonpregnant subjects. Here, we determined bidirectional transfer of pritelivir across dually perfused term human placental lobule and its effect on placental tissue viability and functionality ex vivo. We also assessed potential cytotoxicity of pritelivir in vitro using human choriocarcinoma-derived trophoblast-like cells (BeWo, b30 clone) and human umbilical vein endothelial cells. Our data demonstrated the transfer of pritelivir across the placenta ex vivo from the maternal to the fetal circuit and vice versa. Clearance index of pritelivir (ie, the transfer of pritelivir normalized to the transfer of a freely diffusible reference compound antipyrine) in the fetal-to-maternal direction (0.98 ± 0.07, n = 9) exceeded its clearance index in the maternal-to-fetal direction (0.86 ± 0.08, n = 9, P = .006), suggesting involvement of mechanisms other than diffusion in the placental disposition of this drug (possibly, efflux membrane transporters P-glycoprotein and breast cancer resistance protein that accept pritelivir as a substrate in vitro). Although our data suggested plausible fetal exposure to the drug, pritelivir did not affect the production of lactate, the consumption of glucose and oxygen, and the release of human chorionic gonadotropin from the perfused placental tissue, indicating its favorable safety profile. Moreover, pritelivir did not alter the viability of the tested cells in vitro. SIGNIFICANCE STATEMENT: Preclinical data on placental disposition of pritelivir are crucial to advance the development of this novel antiherpetic drug for its use in pregnancy. The results revealed bidirectional transfer of pritelivir across dually perfused term human placenta ex vivo. Although fetal exposure to the drug is plausible, pritelivir did not impact the viability and functionality of the placenta. Higher transplacental transfer of pritelivir in the fetal-to-maternal direction rather than maternal-to-fetal direction suggested the involvement of placental membrane transporters.