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

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          ABSTRACT

          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 in vivo 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 ( n = 10) and DTG ( n = 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.

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          Author and article information

          Journal
          Antimicrob Agents Chemother
          Antimicrob. Agents Chemother
          aac
          aac
          AAC
          Antimicrobial Agents and Chemotherapy
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0066-4804
          1098-6596
          27 March 2017
          24 May 2017
          June 2017
          : 61
          : 6
          : e02213-16
          Affiliations
          [a ]Emory University, School of Medicine, Atlanta, Georgia, USA
          [b ]Department of Gynecology and Obstetrics, Division of Maternal Fetal Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
          [c ]Department of Pediatrics, Division of Infectious Diseases, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
          [d ]Department of Pediatrics, Center for AIDS Research, Laboratory of Biochemical Pharmacology, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
          [e ]Department of Pediatrics, Division of Neonatology, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts
          Author notes
          Address correspondence to Bassam H. Rimawi, bassamrimawi@ 123456yahoo.com .

          Citation Rimawi BH, Johnson E, Rajakumar A, Tao S, Jiang Y, Gillespie S, Schinazi RF, Mirochnick M, Badell ML, Chakraborty R. 2017. Pharmacokinetics and placental transfer of elvitegravir, dolutegravir, and other antiretrovirals during pregnancy. Antimicrob Agents Chemother 61:e02213-16. https://doi.org/10.1128/AAC.02213-16.

          Author information
          http://orcid.org/0000-0002-8178-9212
          Article
          PMC5444129 PMC5444129 5444129 02213-16
          10.1128/AAC.02213-16
          5444129
          28348149
          40a58623-c0f6-41de-848b-4ea79fe5dce6
          Copyright © 2017 American Society for Microbiology.

          All Rights Reserved.

          History
          : 14 October 2016
          : 29 January 2017
          : 14 March 2017
          Page count
          Figures: 1, Tables: 3, Equations: 0, References: 32, Pages: 8, Words: 5149
          Funding
          Funded by: IMPAACT
          Award ID: HHSN275701300003C
          Award Recipient : Martina L. Badell
          Funded by: IMPACCT
          Award ID: HHSN275701300003C
          Award Recipient : Rana Chakraborty
          Funded by: CFAR
          Award ID: NIH5P30-AI-50409
          Award Recipient : Raymond F. Schinazi
          Categories
          Antiviral Agents
          Custom metadata
          June 2017

          HIV-1,elvitegravir,dolutegravir,integrase inhibitors,pharmacokinetics,placental transfer,pregnancy

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