Schipani, A;
Egan, D;
Dickinson, L;
Davies, G;
Boffito, M;
Youle, M;
Khoo, S. H.;
... Owen, A; + view all
(2012)
Estimation of the effect of SLCO1B1 polymorphisms on lopinavir plasma concentration in HIV-Infected Adults.
Antiviral Therapy
, 17
(5)
pp. 861-868.
10.3851/IMP2095.
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Abstract
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. Conclusion—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.
| Type: | Article |
|---|---|
| Title: | Estimation of the effect of SLCO1B1 polymorphisms on lopinavir plasma concentration in HIV-Infected Adults |
| Identifier: | PMCID:3443796 |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3851/IMP2095 |
| Publisher version: | http://dx.doi.org/10.3851/IMP2095 |
| Language: | English |
| Additional information: | The published manuscript is available at Antiviral Therapy via http://www.intmedpress.com/journals/avt/article.cfm?id=2095&pid=48&sType=AVT |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1473615 |
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