Abstract
Purpose
To demonstrate the bioequivalence of the planned maleate salt-based commercial glasdegib tablet formulation [International Council for Harmonization (ICH) glasdegib] to the clinical di-hydrochloride (di-HCl) salt-based glasdegib formulation (di-HCl glasdegib). Additionally, to estimate the effects of a high-fat, high-calorie meal and proton-pump inhibitor (PPI) on the pharmacokinetics of ICH glasdegib.
Methods
This Phase I open-label study (ClinicalTrials.gov: NCT03130556) enrolled 24 healthy subjects to receive two different tablet formulations of single-dose 100-mg glasdegib under fasted conditions. A subset of healthy volunteers (n = 12) received single-dose 100-mg ICH glasdegib following a high-fat, high-calorie meal or concurrently with a PPI (rabeprazole).
Results
The adjusted geometric mean ratio (ICH glasdegib:di-HCl glasdegib) and 90% confidence intervals (CI) of area under the plasma concentration–time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 104.0% (99.7‒108.5%) and 101.6% (96.1‒107.4%), respectively, within the acceptance range for bioequivalence (80‒125%). The adjusted geometric mean ratio (90% CIs) for AUCinf and Cmax under fed conditions were 84.3% (78.6‒90.6%) and 69.0% (61.8‒77.0%), respectively, relative to fasted conditions. When ICH glasdegib was administered concurrently with the PPI, the adjusted geometric mean ratio (90% CI) of AUCinf and Cmax were 100.6% (93.2‒108.6%) and 80.5% (70.7‒91.6%), respectively, relative to fasted conditions. Glasdegib was generally well tolerated under all conditions studied.
Conclusions
The ICH glasdegib tablet formulation was bioequivalent to the clinical di-HCl formulation under fasted conditions. A high-fat, high-calorie meal or concurrent PPI treatment had a minimal effect on glasdegib exposure, and was not considered clinically meaningful.
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