title: Placental transfer of the HIV integrase inhibitor dolutegravir in an ex vivo human cotyledon perfusion model.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Stein
authors.initials: S
authors.lastname: Schalkwijk
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Greupink
authors.affiliation: Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Angela P
authors.initials: AP
authors.lastname: Colbers
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Alfons C
authors.initials: AC
authors.lastname: Wouterse
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Vivienne G M
authors.initials: VG
authors.lastname: Verweij
authors.affiliation: Department of Obstetrics and Gynecology, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: van Drongelen
authors.affiliation: Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Marga
authors.initials: M
authors.lastname: Teulen
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: van den Oetelaar
authors.affiliation: Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands.
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen 6500 HB, The Netherlands frans.russel@radboudumc.nl.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D002853:Chromatography, Liquid; D018548:Cotyledon / Q000378:metabolism*; D005260:Female; D019428:HIV Integrase Inhibitors / Q000493:pharmacokinetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics*; D006801:Humans; D008954:Models, Biological; D010078:Oxazines; D010477:Perfusion; D010879:Piperazines; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011728:Pyridones; D053719:Tandem Mass Spectrometry; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir