title: Population approach to analyze the pharmacokinetics of free and total lopinavir in HIV-infected pregnant women and consequences for dose adjustment.
abstract: The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy.
authors.affiliation: EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France florisfauchet@gmail.com.
authors.forename: Floris
authors.initials: F
authors.lastname: Fauchet
authors.affiliation: EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France Service de Pharmacologie Clinique, AP-HP, Groupe Hospitalier Paris Centre, Paris, France CIC-0901 INSERM, Cochin-Necker, Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Treluyer
authors.affiliation: EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Illamola
authors.affiliation: EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Pressiat
authors.affiliation: EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Lui
authors.affiliation: EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Valade
authors.affiliation: INSERM, Centre for Research in Epidemiology and Population Health, U1018, Equipe VIH et IST, Le Kremlin-Bicêtre, France AP-HP, Hôpital Louis Mourier, HUPNVS, Service de Gynécologie et d'Obstétrique, Colombes, France Université Diderot Paris 7, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mandelbrot
authors.affiliation: INSERM, Centre for Research in Epidemiology and Population Health, U1018, Equipe VIH et IST, Le Kremlin-Bicêtre, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Lechedanec
authors.affiliation: INSERM, Centre for Research in Epidemiology and Population Health, U1018, Equipe VIH et IST, Le Kremlin-Bicêtre, France AP-HP, Hôpital Bicêtre, Service d'Epidemiologie et Santé Publique, Le Kremlin-Bicêtre, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delmas
authors.affiliation: EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France AP-HP, Hôpital Necker, Unité d'Immunologie Hématologie Pédiatrique, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.affiliation: INSERM, Centre for Research in Epidemiology and Population Health, U1018, Equipe VIH et IST, Le Kremlin-Bicêtre, France AP-HP, Hôpital Bicêtre, Service d'Epidemiologie et Santé Publique, Le Kremlin-Bicêtre, France.
authors.forename: Josiane
authors.initials: J
authors.lastname: Warszawski
authors.affiliation: EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France CIC-0901 INSERM, Cochin-Necker, Paris, France.
authors.forename: Saik
authors.initials: S
authors.lastname: Urien
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS 943, Pierre Louis Institute of Epidemiology and Public Health, Paris, France AP-HP, GH Pitié Salpêtrière, Maladies Infectieuses, Paris, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Tubiana
authors.affiliation: EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Service de Pharmacologie Clinique, AP-HP, Groupe Hospitalier Paris Centre, Paris, France.
authors.forename: Déborah
authors.initials: D
authors.lastname: Hirt
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D060005:Genotyping Techniques; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D061466:Lopinavir