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

SummaryAIMS 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 glasdegib alone or following once-daily pre-treatment with 600 mg rifampin administered once daily. 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 (m2) –1, respectively. When dosed alone, glasdegib geometric mean (% coefficient of variation) area under the plasma concentration–time curve from time zero to infinity (AUCinf) was 8,145 ng × h ml–1 (23%) and maximum observed concentration (Cmax) was 703.2 ng ml–1 (19%). With rifampin, glasdegib AUCinf and Cmax decreased, with an adjusted geometric mean ratio (90% confidence interval) 29.66% (26.17–33.62) for AUCinf and 64.71% (57.21–73.19) for Cmax. 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 Cmax remained similar (1.50 vs. 1.25 hours) in the presence of rifampin. Acne was the only adverse event reported, and considered drug-unrelated. CONCLUSIONS Co-administration of rifampin expectedly decreased glasdegib AUCinf and Cmax 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)