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 ) , respectively. When dosed alone, glasdegib geometric mean (% coefficient of variation) area under the plasma concentration-time curve from time zero to infinity (AUC ) was 8145 ng × h ml (23%) and maximum observed concentration (C ) was 703.2 ng ml (19%). With rifampin, glasdegib AUC and C decreased, with an adjusted geometric mean ratio (90% confidence interval) 29.66% (26.17-33.62) for AUC and 64.71% (57.21-73.19) for C . 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 , whereas median time to C 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 and C 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).