| Estimation of the effect of SLCO1B1 polymorphisms on lopinavir plasma concentration in HIV-infected adults. | |
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MedLine Citation:
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PMID: 22477766 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: The organic anion transporting polypeptides (OATP)/SLCO family represents an important class of hepatic drug uptake transporters that mediate the sodium independent transport of a diverse range of amphipathic organic compounds, including the protease inhibitors. The SLCO1B1 521T>C (rs4149056) single nucleotide polymorphism (SNP) has been consistently associated with reduced transport activity in vivo, and we previously showed an association of this polymorphism with lopinavir plasma concentrations. The aim of this study was to develop a population pharmacokinetic (PK) model to quantify the impact of 521T>C. METHODS: A population PK analysis was performed with 594 plasma samples from 375 patients receiving lopinavir/ritonavir. Non-linear mixed effects modelling was applied to explore the effects of SLCO1B1 521T>C and patient demographics. Simulations of the lopinavir concentration profile were performed with different dosing regimens considering the different alleles. RESULTS: A one-compartment model with first-order absorption best described the data. Population clearance was 5.67 l/h with inter-patient variability of 37%. Body weight was the only demographic factor influencing clearance, which increased 0.5 l/h for every 10 kg increase. Homozygosity for the C allele was associated with a 37% lower clearance, and 14% for heterozygosity, which were statistically significant. CONCLUSIONS: These data show an association between SLCO1B1 521T>C and lopinavir clearance. The association is likely to be mediated through reduced uptake by hepatocytes leading to higher plasma concentrations of lopinavir. Further studies are now required to confirm the association and to assess the influence of other polymorphisms in the SLCO family on lopinavir PK. |
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Authors:
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Alessandro Schipani; Deirdre Egan; Laura Dickinson; Gerry Davies; Marta Boffito; Mike Youle; Saye H Khoo; David J Back; Andrew Owen |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-04-04 |
Journal Detail:
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Title: Antiviral therapy Volume: 17 ISSN: 2040-2058 ISO Abbreviation: Antivir. Ther. (Lond.) Publication Date: 2012 |
Date Detail:
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Created Date: 2012-08-24 Completed Date: 2013-01-15 Revised Date: 2013-02-28 |
Medline Journal Info:
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Nlm Unique ID: 9815705 Medline TA: Antivir Ther Country: England |
Other Details:
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Languages: eng Pagination: 861-8 Citation Subset: IM |
Affiliation:
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Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Anti-HIV Agents / administration & dosage, blood*, therapeutic use Computer Simulation Female Genotype HIV Infections / blood*, drug therapy, genetics* Humans Lopinavir / administration & dosage, blood*, therapeutic use Male Middle Aged Models, Statistical Organic Anion Transporters / genetics* Polymorphism, Single Nucleotide* Young Adult |
| Grant Support | |
ID/Acronym/Agency:
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083851//Wellcome Trust; 083851/Z/07/Z//Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Anti-HIV Agents; 0/Lopinavir; 0/Organic Anion Transporters; 0/SLCO1B1 protein, human |
| Comments/Corrections | |
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