Placental transfer of the HIV integrase inhibitor dolutegravir in an ex vivo human cotyledon perfusion model.

OBJECTIVES: Data on fetal exposure to antiretroviral agents during pregnancy are important to estimate their potential for prevention of mother-to-child transmission (PMTCT) and possible toxicity. For the recently developed HIV integrase inhibitor dolutegravir, clinical data on fetal disposition are not yet available. Dual perfusion of a single placental lobule (cotyledon) provides a useful ex vivo model to predict the in vivo maternal-to-fetal transfer of this drug. The aim of this study was to estimate the transfer of dolutegravir across the human term placenta, using a dual-perfusion cotyledon model. METHODS: After cannulation of the cotyledons (n = 6), a fetal circulation of 6 mL/min and maternal circulation of 12 mL/min were initiated. The perfusion medium consisted of Krebs-Henseleit buffer (pH = 7.2-7.4) supplemented with 10.1 mM glucose, 30 g/L human serum albumin and 0.5 mL/L heparin 5000IE. Dolutegravir was administered to the maternal circulation (∼ 4.2 mg/L) and analysed by UPLC-MS/MS. RESULTS: After 3 h of perfusion, the mean ± SD fetal-to-maternal (FTM) concentration ratio of dolutegravir was 0.6 ± 0.2 and the mean ± SD concentrations in the maternal and fetal compartments were 2.3 ± 0.4 and 1.3 ± 0.3 mg/L, respectively. CONCLUSIONS: Dolutegravir crosses the blood-placental barrier with a mean FTM concentration ratio of 0.6. Compared with other antiretroviral agents, placental transfer of dolutegravir is moderate to high. These data suggest that dolutegravir holds clinical potential for pre-exposure prophylaxis and consequently PMTCT, but also risk of fetal toxicity.

A multi-institutional study benchmarking the zebrafish developmental assay for prediction of embryotoxic plasma concentrations from rat embryo-fetal development studies.

Predicting embryotoxicity of pharmaceutical compounds or industrial chemicals is crucial for public safety. Conventional studies which monitor embryo-fetal development in rats and rabbits are costly and time consuming. Alternative assays which are simpler and less costly are being pursued. The purpose of this research was to assess the capacity for the zebrafish development assay to predict mammalian plasma levels that are embryotoxic. Previously published data on rat plasma levels associated with embryotoxicity were used to guide concentration ranges for each of 25 chemicals dissolved in the media bathing developing zebrafish embryos. Embryotoxic media concentrations were compared to embryotoxic rat plasma concentrations. Assays were conducted in parallel at multiple sites as a consortium effort through the Health and Environmental Sciences Institute (HESI). Considering results from all sites, the zebrafish embryo development assay predicted (within 1-log) the rat maternal exposure levels associated with embryotoxicity 75% of the time.