Placental Transfer of the HIV Integrase Inhibitor Dolutegravir in an Ex Vivo Human Cotyledon Perfusion Model.

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.After cannulation of the cotyledons (naEuroS=aEuroS6), a fetal circulation of 6 mL/min and maternal circulation of 12 mL/min were initiated. The perfusion medium consisted of Krebs-Henseleit buffer (pHaEuroS=aEuroS7.2-7.4) 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 (similar to 4.2 mg/L) and analysed by UPLC-MS/MS.After 3 h of perfusion, the meanaEuroS +/- aEuroSSD fetal-to-maternal (FTM) concentration ratio of dolutegravir was 0.6aEuroS +/- aEuroS0.2 and the meanaEuroS +/- aEuroSSD concentrations in the maternal and fetal compartments were 2.3aEuroS +/- aEuroS0.4 and 1.3aEuroS +/- aEuroS0.3 mg/L, respectively.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.