title: Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models.
abstract: OBJECTIVE
  Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively.
  
  
  METHODS
  Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models.
  
  
  RESULTS
  Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo.
  
  
  CONCLUSIONS
  The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.
authors.forename: Maïlys
authors.initials: M
authors.lastname: De Sousa Mendes
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.|Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Broca-Hôtel-Dieu-Dieu, 75014, Paris, France.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hirt
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vinot
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Valade
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.|Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Broca-Hôtel-Dieu-Dieu, 75014, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Lui
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Pressiat
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.
authors.forename: Naïm
authors.initials: N
authors.lastname: Bouazza
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.
authors.forename: Frantz
authors.initials: F
authors.lastname: Foissac
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.|AP-HP, Hôpital Necker-Enfants-Malades, Unité d'Immunologie, Hématologie et Rhumatologie Pédiatriques, 75015, Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Blanche
authors.affiliation: AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Pharmacologie, 75018, Paris, France.
authors.forename: Minh Patrick
authors.initials: MP
authors.lastname: Lê
authors.affiliation: AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Pharmacologie, 75018, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Peytavin
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.|Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Broca-Hôtel-Dieu-Dieu, 75014, Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Treluyer
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.|CIC-1419 Inserm, Cochin-Necker, Paris, France.
authors.forename: Saik
authors.initials: S
authors.lastname: Urien
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Unité de Recherche Clinique Paris Centre, 75006, Paris, France.|Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Broca-Hôtel-Dieu-Dieu, 75014, Paris, France.
authors.forename: Sihem
authors.initials: S
authors.lastname: Benaboud
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D000068679:Emtricitabine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005312:Fetal Blood; D005333:Fetus / Q000378:metabolism*; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D008954:Models, Biological; D010477:Perfusion; D010920:Placenta / Q000378:metabolism*; D021041:Placental Circulation / Q000502:physiology*; D011237:Predictive Value of Tests; D011247:Pregnancy; D000068698:Tenofovir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir; D000068679:Emtricitabine
keywords: PBPK; emtricitabine; fetus; pharmacokinetics; pregnancy; tenofovir