1. The pharmacogenetics of OATP1B1 variants and their impact on the pharmacokinetics and efficacy of elbasvir/grazoprevir.
- Author
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Guo Z, Caro L, Robertson MN, Hwang P, Hoover P, Wudarski C, Maiuri K, Wang YH, Mogg R, Mehrotra DV, Blanchard R, and Shaw PM
- Subjects
- Antiviral Agents administration & dosage, Antiviral Agents therapeutic use, Benzofurans administration & dosage, Benzofurans therapeutic use, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Drug Combinations, Female, Hepacivirus genetics, Hepatitis C genetics, Humans, Imidazoles administration & dosage, Imidazoles therapeutic use, Logistic Models, Male, Middle Aged, Pharmacogenetics, Quinoxalines administration & dosage, Quinoxalines therapeutic use, Retrospective Studies, Treatment Outcome, Antiviral Agents blood, Benzofurans blood, Hepatitis C drug therapy, Imidazoles blood, Liver-Specific Organic Anion Transporter 1 genetics, Polymorphism, Single Nucleotide, Quinoxalines blood
- Abstract
Aim: To evaluate the effect of SLCO1B1 genetic variants on grazoprevir pharmacokinetics and efficacy. Methods: A retrospective analysis of 1578 hepatitis C virus-infected participants from ten Phase II/III clinical trials. Results: Relative to noncarriers of the risk allele, geometric mean ratios (95% CI) of grazoprevir area under curve (AUC)
0-24 were: rs4149056 (risk allele C), one copy, 1.13 (1.06-1.21), two copies, 1.43 (1.16-1.77); and rs11045819 (risk allele A), one copy, 0.93 (0.87-1.00); two copies, 0.78 (0.61-1.00). The rs2306283 variant was not associated with grazoprevir exposure. None of the SLCO1B1 variants were associated with sustained virologic response. Conclusion: Genetic variants in SLCO1B1 were associated with modest changes in grazoprevir pharmacokinetics, but not with meaningful differences in efficacy.- Published
- 2019
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