Abstract
Purpose
This phase I open-label study investigated the oral bioavailability of two novel maleate salt-based glasdegib (PF-04449913) tablet formulations (small- and large-particle size) relative to the current clinical formulation (diHCl salt-based). In addition, the effect of a gastric pH-altering agent (rabeprazole) and food on the pharmacokinetics of the large-particle size formulation of glasdegib were evaluated. The pharmacokinetics of glasdegib oral solution was also assessed.
Methods
Thirty-four healthy subjects received glasdegib 100 mg as three different formulations in the fasted state (diHCl salt or small- or large-particle size maleate formulation); 13 received the large-particle maleate formulation (fed), and 14 concurrently with rabeprazole (fasted); six subjects received glasdegib 50 mg oral solution (fasted).
Results
For both new tablet formulations of glasdegib, ratios (Test:Reference) of adjusted geometric means (90% confidence interval) of area under the concentration–time curve from 0 to infinity and maximum plasma concentration were within 80–125% compared with the diHCl formulation (fasted). For the large-particle size formulation (fed), these ratios were 86.3% (81.0–92.0%) and 75.7% (65.3–87.7%), respectively, compared with fasted. When the large-particle maleate formulation was administered concurrently with rabeprazole versus alone (fasted), these ratios were 111.9% (102.8–121.9%) and 87.2% (75.9–100.3%), respectively. The pharmacokinetics of oral solution was similar to the tablet.
Conclusions
The maleate salt-based tablet formulations were bioequivalent to the diHCl tablet formulation. The extent of the observed effect of a high-fat, high-calorie meal or concurrent rabeprazole treatment on glasdegib exposure is not considered clinically meaningful.
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Funding
This study was sponsored by Pfizer and was conducted at the Pfizer Clinical Research Unit in New Haven, CT. Medical writing support was provided by David Sunter at Engage Scientific Solutions and was funded by Pfizer.
Conflict of interest
Nagdeep Giri, Robert R. LaBadie, Joseph F. Krzyzaniak, Hong Jiang, Brian Hee, Yali Liang, and M. Naveed Shaik are employees of Pfizer Inc and hold stock and/or stock options in Pfizer Inc; Lisa H. Lam was a paid postdoctoral fellow with Pfizer through the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego during the conduct of this study and development of this manuscript.
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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.
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Informed consent was obtained from all individual participants included in the study.
Additional information
This study was sponsored by Pfizer and was conducted at the Pfizer Clinical Research Unit in New Haven, CT, USA.
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Giri, N., Lam, L.H., LaBadie, R.R. et al. Evaluation of the effect of new formulation, food, or a proton pump inhibitor on the relative bioavailability of the smoothened inhibitor glasdegib (PF-04449913) in healthy volunteers. Cancer Chemother Pharmacol 80, 1249–1260 (2017). https://doi.org/10.1007/s00280-017-3472-9
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DOI: https://doi.org/10.1007/s00280-017-3472-9