Evaluation of the effect of rifampin on the pharmacokinetics of the Smoothened inhibitor glasdegib in healthy volunteers

AimsThis study aimed to evaluate the effect of a strong CYP3A inducer, rifampin, on glasdegib pharmacokinetics in healthy volunteers. MethodsIn an open-label, fixed-sequence, two-period Phase 1 study, subjects received a single 100-mg oral dose of glasdegib alone or following once-daily pre-treatment with 600mg rifampin. Glasdegib pharmacokinetics were calculated using a noncompartmental analysis. ResultsTwelve healthy male volunteers (3 whites, 5 blacks and 4 others) were enrolled in the study. Mean age, weight, height and body mass index was 37.8years, 83.0kg, 177.3cm and 26.5kg (m(2)) (-1), respectively. When dosed alone, glasdegib geometric mean (% coefficient of variation) area under the plasma concentration-time curve from time zero to infinity (AUC(inf)) was 8145ng x h ml(-1) (23%) and maximum observed concentration (C-max) was 703.2ngml(-1) (19%). With rifampin, glasdegib AUC(inf) and C-max decreased, with an adjusted geometric mean ratio (90% confidence interval) 29.66% (26.17-33.62) for AUC(inf) and 64.71% (57.21-73.19) for C-max. Mean terminal half-life decreased from 13.39 to 5.11hours, geometric mean apparent oral clearance increased from 12.27 to 41.38lh(-1), whereas median time to C-max remained similar (1.50 vs. 1.25hours) in the presence of rifampin. All adverse events (n=29) were mild in severity and resolved by the end of the study. ConclusionsCo-administration of rifampin expectedly decreased glasdegib AUC(inf) and C-max by similar to 70% and similar to 35%, respectively. These results will help to formulate recommendations for dosing strategies in combination with CYP3A inducers in situations where co-administration may be necessary. ( identifier: NCT02430545).