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Antimicrob Agents Chemother. 2015 Sep;59(9):5727-35. doi: 10.1128/AAC.00863-15. Epub 2015 Jul 6.

Population approach to analyze the pharmacokinetics of free and total lopinavir in HIV-infected pregnant women and consequences for dose adjustment.

Author information

1
EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France florisfauchet@gmail.com.
2
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.
3
EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France.
4
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.
5
INSERM, Centre for Research in Epidemiology and Population Health, U1018, Equipe VIH et IST, Le Kremlin-Bicêtre, France.
6
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.
7
EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France AP-HP, Hôpital Necker, Unité d'Immunologie Hématologie Pédiatrique, Paris, France.
8
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.
9
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.
10
EA 08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Service de Pharmacologie Clinique, AP-HP, Groupe Hospitalier Paris Centre, Paris, France.

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.

PMID:
26149996
PMCID:
PMC4538471
DOI:
10.1128/AAC.00863-15
[Indexed for MEDLINE]
Free PMC Article

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