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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

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

Nagdeep Giri, Lisa H Lam, Robert R LaBadie, Joseph F Krzyzaniak, Hong Jiang, Brian Hee, Yali Liang, M Naveed Shaik

Cancer Chemother Pharmacol. 2017 Dec;80(6):1249-1260.

PMID: 29086063

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
ALP1095173275	PF-04449913 maleate salt		1095173-27-5 (free base)	Price

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