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

Summary

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 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 (AUC_inf) was 8,145 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. Acne was the only adverse event reported, and considered drug-unrelated.

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)

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