Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

被引：14

作者：

Fauchet, Floris ^{[1
,2
]}

Treluyer, Jean-Marc ^{[1
,2
,3
,4
]}

Illamola, Silvia M. ^{[1
,2
]}

Pressiat, Claire ^{[1
,2
]}

Lui, Gabrielle ^{[1
,2
]}

Valade, Elodie ^{[1
,2
]}

Mandelbrot, Laurent ^{[5
,6
,7
]}

Lechedanec, Jerome ^{[5
]}

Delmas, Sandrine ^{[5
,8
]}

Blanche, Stephane ^{[1
,9
]}

Warszawski, Josiane ^{[5
,8
]}

Urien, Saik ^{[1
,2
,4
]}

Tubiana, Roland ^{[10
,11
]}

Hirt, Deborah ^{[1
,3
]}

机构：

[1] Univ Paris 05, EA 08, Sorbonne Paris Cite, Paris, France

[2] Hop Tarnier, AP HP, Unite Rech Clin, Paris, France

[3] Grp Hosp Pris Ctr, AP HP, Serv Pharmacol Clin, Paris, France

[4] INSERM, CIC 0901, Paris, France

[5] Equipe VIH & IST, Ctr Res Epidemiol & Populat Hlth, INSERM, U1018, Le Kremlin Bicetre, France

[6] HUPNVS, Hop Louis Mourier, AP HP, Serv Gynecol & Obstet, Colombes, France

[7] Univ Paris 07, Paris, France

[8] Hop Bicetre, AP HP, Serv Epidemiol & Sante Publ, Le Kremlin Bicetre, France

[9] Hop Necker Enfants Malad, AP HP, Unite Immunol Hematol Pediat, Paris, France

[10] Univ Paris 06, Sorbonne Univ, Pierre Louis Inst Epidemiol & Publ Hlth, INSERM,UMRS 943, Paris, France

[11] GH Pitie Salpetriere, AP HP, Malad Infect, Paris, France

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2015年 / 59卷 / 09期

关键词：

PLASMA-CONCENTRATIONS; PROTEASE INHIBITORS; MITOCHONDRIAL DYSFUNCTION; ANTIRETROVIRAL DRUGS; UNINFECTED CHILDREN; NUCLEOSIDE ANALOGS; EXPOSURE; RITONAVIR; BINDING; LOPINAVIR/RITONAVIR;

D O I：

10.1128/AAC.00863-15

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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.

引用

页码：5727 / 5735

页数：9

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