Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy

• Published in: Antimicrobial agents and chemotherapy Vol. 61; no. 6
• Main Authors: Rimawi, Bassam H, Johnson, Erica, Rajakumar, Augustine, Tao, Sijia, Jiang, Yong, Gillespie, Scott, Schinazi, Raymond F, Mirochnick, Mark, Badell, Martina L, Chakraborty, Rana
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.06.2017
• Subjects: Adolescent; Adult; Anti-Retroviral Agents; Anti-Retroviral Agents - pharmacokinetics; Antiviral Agents; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 3-Ring - pharmacokinetics; HIV Infections - drug therapy; HIV Infections - metabolism; HIV-1 - drug effects; HIV-1 - pathogenicity; Humans; Lentivirus; Placenta; Placenta - metabolism; Pregnancy; Quinolones; Quinolones - pharmacokinetics; Retroviridae; Young Adult; HIV-1; integrase inhibitors; placental transfer; elvitegravir; pregnancy; pharmacokinetics; dolutegravir
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02213-16

The integrase inhibitors elvitegravir (EVG) and dolutegravir (DTG) rapidly decrease the plasma HIV-1 viral load, a key factor in the prevention of maternal-to-fetal transmission of HIV-1. No data have been reported on the concentrations of these drugs in cord blood, maternal peripheral blood mononuclear cells (PBMCs), or placental tissue in pregnant women. We present pharmacokinetic data on antiretrovirals (ARV) within maternal and cord blood and within placentae from HIV-1-infected pregnant women. Maternal blood and cord blood were obtained from women receiving EVG, cobicistat, tenofovir disoproxil fumarate, and emtricitabine as a single fixed-dose combination formulation or DTG as part of a combination regimen. Plasma and PBMCs from maternal and cord blood were obtained along with villous placental samples. Drug concentrations were simultaneously determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Utilizing medians and ranges to interpret our data, we compared the drug concentration ratios between different matrices (maternal and cord blood plasma, PBMCs, and placenta). All five agents transferred from maternal into fetal circulation via the placenta. Concentration ratios for EVG, cobicistat, tenofovir, and emtricitabine ( = 10) and DTG ( = 3) were determined between cord plasma and placenta, cord and maternal plasma, and cord PBMCs and maternal PBMCs. TFV moves from maternal plasma through the placenta to the cord blood and then into cord PBMCs, where it is phosphorylated into its active forms (TFV diphosphate). These five ARVs were detected in each of the compartments, highlighting transfer of these agents from the maternal into the fetal circulation.