RESUMO
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.
Assuntos
Antivirais/sangue , Benzofuranos/sangue , Hepatite C/tratamento farmacológico , Imidazóis/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Polimorfismo de Nucleotídeo Único , Quinoxalinas/sangue , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Benzofuranos/administração & dosagem , Benzofuranos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Combinação de Medicamentos , Feminino , Hepacivirus/genética , Hepatite C/genética , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Quinoxalinas/administração & dosagem , Quinoxalinas/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
A major pathway of elimination of the prostaglandin D2 receptor 1 antagonist laropiprant in humans is by uridine diphosphate-glucuronosyltransferase (UGT)-mediated biotransformation. In this study, liver and kidney relative activity factors were developed for UGT1A1, 1A9 and 2B7 to allow for in vitro-in vivo extrapolation of intrinsic clearance data to whole organ clearance using recombinant human UGT isoforms applying this to laropiprant as a model substrate. The total body metabolic clearance of laropiprant determined using this approach (5.0 L/hr) agreed well with the value determined in vivo following intravenous administration to healthy human volunteers (5.1 L/hr). The results suggest that approximately 36%, 36% and 28% of the hepatic metabolic clearance of laropiprant was mediated by UGT1A1, 1A9 and 2B7, respectively. Likewise, 80% and 20% of the renal metabolic clearance was mediated by UGT1A9 and 2B7, respectively. Furthermore, the data suggested that the contribution of the kidney to the overall total metabolic clearance was minor relative to the liver (≈ 12%).
