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

Aims This study aimed to evaluate the effect of a strong CYP3A inducer, rifampin, on glasdegib pharmacokinetics in healthy volunteers. Methods In 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 600 mg rifampin. Glasdegib pharmacokinetics were calculated using a noncompartmental analysis. Results Twelve healthy male volunteers (3 whites, 5 blacks and 4 others) were enrolled in the study. Mean age, weight, height and body mass index was 37.8 years, 83.0 kg, 177.3 cm and 26.5 kg (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 8145 ng × h ml −1 (23%) and maximum observed concentration ( C max ) was 703.2 ng ml −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 5.11 hours, geometric mean apparent oral clearance increased from 12.27 to 41.38 l h −1 , whereas median time to C max remained similar (1.50 vs. 1.25 hours) in the presence of rifampin. All adverse events ( n  = 29) were mild in severity and resolved by the end of the study. Conclusions Co‐administration of rifampin expectedly decreased glasdegib AUC inf and C max by ~70% and ~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. ( clinicaltrials.gov identifier: NCT02430545).