RESUMO
Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open-label, three-period, fixed-sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed-dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single-dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole. Geometric mean ratios (GMRs) of grazoprevir AUC(0,∞), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 0.89-1.17. Similarly, GMRs of elbasvir AUC(0,∞), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 1.02-1.11. These results indicate that gastric acid-reducing agents do not modify the pharmacokinetics of elbasvir or grazoprevir in a clinically relevant manner and may be coadministered with elbasvir/grazoprevir in HCV-infected patients without restriction.
Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/farmacocinética , Antivirais/farmacocinética , Benzofuranos/farmacocinética , Famotidina/farmacocinética , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacocinética , Quinoxalinas/farmacocinética , 2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Adulto , Amidas , Antivirais/efeitos adversos , Antivirais/farmacologia , Benzofuranos/efeitos adversos , Benzofuranos/sangue , Benzofuranos/farmacologia , Carbamatos , Ciclopropanos , Demografia , Interações Medicamentosas , Famotidina/efeitos adversos , Famotidina/farmacologia , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/sangue , Imidazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Pantoprazol , Quinoxalinas/efeitos adversos , Quinoxalinas/sangue , Quinoxalinas/farmacologia , Sulfonamidas , Fatores de Tempo , Adulto JovemRESUMO
GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0-2.5 h and mean apparent terminal half-life was 22-32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure-response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy.