The impact of SLCO1B1 polymorphisms on the plasma concentration of lopinavir and ritonavir in HIV‐infected men

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• There is large interindividual variability in the pharmacokinetics of protease inhibitors (PIs) among human immunodeficiency virus (HIV)-infected individuals under highly active antiretroviral therapy. • Protease inhibitor have been recently reported to be substrates of the SLCO1B1/OATP1 drug transporter.• A single nucleotide polymorphism (SNP) in the SLCO1B1 gene (521T→C) was associated with plasma levels of lopinavir in HIV-infected individuals. WHAT THIS STUDY ADDS• Data on the impact of three SLCO1B1 SNPs (521T→C, 388A→G, 463C→A) on the trough plasma concentration of lopinavir and ritonavir in a cohort of 99 adult HIV-infected Brazilian men under stable highly active antiretroviral therapy.• Evidence that carriers of the 521C allele display significantly higher lopinavir, but not ritonavir plasma concentrations relative to the wild-type TT genotype.• No effect of either 388A→G or 463C→A SNPs on lopinavir or ritonavir plasma concentrations.• Further studies are required to confirm the clinical significance of the association between the SLCO1B1521T→C polymorphism and lopinavir pharmacokinetics. AIMSTo investigate possible associations between three SLCO1B1 single nucleotide polymorphisms (388A→G, 463C→A, 521T→C) and lopinavir/ritonavir plasma concentrations. METHODSThe study included 99 human immunodeficiency virus-infected men on stable highly active antiretroviral therapy containing lopinavir/ritonavir. Trough concentrations of lopinavir and ritonavir in plasma were quantified using liquid chromatography-tandem mass spectrometry. Genotyping of SLCO1B1388A→G, 463C→A and 521T→C polymorphisms was performed by allelic discrimination using real-time polymerase chain reaction. RESULTSThe trough concentration of lopinavir in plasma is significantly associated with SLCO1B1521T→C genotypes (P = 0.03). There is a significant trend for increasing concentrations of lopinavir from TT to TC to CC genotypes (P = 0.02). Carriers of the 521C allele display significantly higher lopinavir plasma concentrations relative to the wild-type TT genotype (P = 0.03). CONCLUSIONSReduced uptake of lopinavir by hepatocytes in carriers of the 521C allele may account for these results, but further studies to confirm the clinical importance of SLCO1B1 polymorphisms in lopinavir pharmacokinetics are warranted.British Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2009 Br J Clin Pharmacol / 69:1 / 95-98 / 95

Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin

“…There are well-replicated associations between CYP2B6 polymorphisms and efavirenz PK (11)(12)(13)(14)(15) and between an SLCO1B1 polymorphism and lopinavir PK (16)(17)(18). An association has been reported between an SLCO1B1 polymorphism and rifampin PK (20,21).…”

“…Genetic polymorphisms reported to predict plasma PK of efavirenz (11)(12)(13)(14)(15), rifampin (20,21), and lopinavir (17,18) were genotyped in duplicate. For efavirenz, CYP2B6 516 G¡T (rs3745274), 983 T¡C (rs28399499), and 15582 C¡T (rs4803419) were assayed using MassARRAY iPLEX Gold (Sequenom Inc., San Diego, CA, USA).…”

“…Efavirenz induces CYP3A enzymes, while lopinavir and ritonavir can inhibit or induce CYP3A (10). In addition, the CYP2B6 genotype is a key determinant of efavirenz concentrations (11)(12)(13)(14)(15), while SLCO1B1 polymorphisms impact lopinavir exposures (16)(17)(18). In this phase I trial, we investigated the safety and PK interactions of PA-824 with efavirenz, lopinavir/r, and rifampin, taking into account pharmacogenetics.…”

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

“…A common SNP in the SLCO1B1 gene, 521T>C, has been associated with higher plasma levels of LPV [64][65][66][67], but the clinical significance is still uncertain and further studies are needed to confirm this association and to assess the impact on LPV pharmacokinetics.…”

Potential role of organic anion transporting polypeptide 1B1 (OATP1B1) in the selective hepatic uptake of hematoporphyrin monomethyl ether isomers

“…Compared with wild-type OATP1B1, c.521T>C was associated with increased systemic exposure to multiple drugs, including oral pravastatin [23,24] , fexofenadine [25] , and lopinavir [26,27] . In addition, the co-administration of OATP1B1 inhibitors may affect the pharmacokinetics of its substrates.…”