Evaluation of the effects of formulation, food, or a proton-pump inhibitor on the pharmacokinetics of glasdegib (PF-04449913) in healthy volunteers: a randomized phase I study

Naveed Shaik, Brian Hee, Hua Wei, Robert R LaBadie, Naveed Shaik, Brian Hee, Hua Wei, Robert R LaBadie

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.

Keywords: Food effect; Formulation; Glasdegib; PF-04449913; Pharmacokinetics; Proton-pump inhibitor.

Conflict of interest statement

Conflict of interest

B. Hee, H. Wei, R. R. LaBadie, and N. Shaik are employees of Pfizer and own Pfizer stock and options.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Data sharing statement

Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Figures

Fig. 1
Fig. 1
Treatment sequence. Healthy volunteers received 100 mg of glasdegib as a single, oral, instant-release formulation tablet. All doses were given in a fasted state (> 10 h) unless otherwise stated. The duration of each period was 6 days following glasdegib administration. N number of subjects, PPI proton-pump inhibitor (rabeprazole)
Fig. 2
Fig. 2
Pharmacokinetics of ICH glasdegib and di-HCl glasdegib. Linear median glasdegib plasma concentration–time profiles for both glasdegib formulations (inset contains same data as semi-log profile)
Fig. 3
Fig. 3
Effect of food on ICH glasdegib. a Linear median glasdegib plasma concentration–time profiles for glasdegib given under fasted and fed conditions (inset contains same data as semi-log profile), b Matchstick plots for change in exposure for each subject when ICH glasdegib is given under fasted and fed conditions for AUCinf, and cCmax
Fig. 4
Fig. 4
Effect of PPI (rabeprazole) on ICH glasdegib. a Linear median glasdegib plasma concentration–time profiles for glasdegib given alone and with a PPI (inset contains same data as semi-log profile), b Matchstick plots for change in exposure for each subject when ICH glasdegib is given with and without a PPI for AUCinf, and cCmax

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