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Free and total plasma levels of lopinavir during pregnancy, at delivery and in postpartum: implication for dosage adjustments in pregnant women.
MedLine Citation:
PMID:  22914504     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Physiological changes associated with pregnancy may alter antiretroviral plasma concentrations and might jeopardize prevention of mother-to-child HIV transmission (MTCT). Lopinavir is one of the protease inhibitors more frequently prescribed during pregnancy in Europe. We described the free and total pharmacokinetics of lopinavir in HIV-infected pregnant and non-pregnant women, and evaluated whether significant alterations in its disposition and protein binding warrant systematic dosage adjustment. METHODS: Plasma samples were collected at first, second and third trimester of pregnancy, at delivery, in umbilical cord and in postpartum. Lopinavir free and total plasma concentrations were measured by HPLC-MS/MS. Bayesian calculations were used to extrapolate total concentrations to trough (C(min)). RESULTS: Forty-two HIV-positive pregnant women and 37 non-pregnant women on lopinavir/ritonavir were included in the study. Compared to postpartum and controls values, total lopinavir C(min) were decreased moderately (31-39%) during pregnancy, and free C(min) minimally, showing significant alteration only at delivery (-35%). However, total and free C(min) remained in all patients above the target concentrations for wild-type virus of 1000 ng/ml, and above the unbound IC(50)(WT) of 0.64-0.77 ng/ml of lopinavir, respectively. Lopinavir free fractions remained higher during pregnancy compared to postpartum and controls, and were influenced by α1-acid-glycoprotein and albumin decrease. Free cord-to-mother ratio (0.43) was 2.7-fold higher than total cord-to-mother ratio (0.16), suggesting higher fetal exposure. CONCLUSIONS: The moderate decrease of total lopinavir concentrations during pregnancy is not associated to proportional decrease in free concentrations. Both reach a nadir at delivery, albeit not to an extent that would put treatment-naïve women at risk of insufficient exposure to the free, pharmacologically active concentrations of lopinavir. No dosage adjustment is therefore needed during pregnancy as it is unlikely to further enhance treatment efficacy but could potentially increase the risk of maternal and fetal toxicity. Nonetheless, in case of viral resistance in treatment-experienced pregnant women, loss of virological control or questionable adherence, it is justified to consider LPV dosage adjustment based on total plasma concentrations measurement.
Authors:
Aurélie Fayet-Mello; Thierry Buclin; Nicole Guignard; Sandra Cruchon; Matthias Cavassini; Claudia Grawe; Erika Gremlich; Karoline Aebi Popp; Flavia Schmid; Chin B Eap; Amalio Telenti; Jérôme Biollaz; Laurent A Decosterd; Begoña Martinez de Tejada;
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-22
Journal Detail:
Title:  Antiviral therapy     Volume:  -     ISSN:  2040-2058     ISO Abbreviation:  Antivir. Ther. (Lond.)     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9815705     Medline TA:  Antivir Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Division of Clinical Pharmacology, University Hospital Lausanne, Lausanne, Switzerland.
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