title: Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women.
abstract: OBJECTIVE
  Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy.
  
  
  METHODS
  Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax ) and oral clearances (CL/F).
  
  
  RESULTS
  PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%).
  
  
  CONCLUSIONS
  Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy.
authors.affiliation: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, unité de recherche clinique Paris centre, 75006, Paris.
authors.forename: Maïlys
authors.identifier: http://orcid.org/0000-0001-5460-4350
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.|Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Broca-Hôtel-Dieu-Dieu, 75014, Paris.
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.|CIC-1419 Inserm, Cochin-Necker, Paris.
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.
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.
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.
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.|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: EA08: Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, unité de recherche clinique Paris centre, 75006, Paris.|Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Broca-Hôtel-Dieu-Dieu, 75014, Paris.
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.|Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Broca-Hôtel-Dieu-Dieu, 75014, Paris.
authors.forename: Sihem
authors.initials: S
authors.lastname: Benaboud
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics*; D003198:Computer Simulation; D000068679:Emtricitabine / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D019259:Lamivudine / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D011247:Pregnancy; D065667:Renal Elimination / Q000502:physiology*; D000068698:Tenofovir / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D019259:Lamivudine; D000068698:Tenofovir; D000068679:Emtricitabine
keywords: PBPK; emtricitabine; lamivudine; pharmacokinetics; pregnancy; tenofovir