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

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 a...

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Published in:Cancer chemotherapy and pharmacology 2017-12, Vol.80 (6), p.1249-1260
Main Authors: Giri, Nagdeep, Lam, Lisa H., LaBadie, Robert R., Krzyzaniak, Joseph F., Jiang, Hong, Hee, Brian, Liang, Yali, Shaik, M. Naveed
Format: Article
Language:English
Subjects:
Adolescent
Adult
Benzimidazoles - pharmacokinetics
Benzimidazoles - therapeutic use
Bioavailability
Biological Availability
Cancer Research
Confidence intervals
Female
Food Analysis
Food-Drug Interactions
Formulations
Healthy Volunteers
Humans
Inhibitors
Male
Medicine
Medicine & Public Health
Middle Aged
Oncology
Original Article
Particle size
pH effects
Pharmacokinetics
Pharmacology
Pharmacology/Toxicology
Phenylurea Compounds - pharmacokinetics
Phenylurea Compounds - therapeutic use
Proton pump inhibitors
Proton Pump Inhibitors - therapeutic use
Reagents
Salts
Young Adult
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Summary: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.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-017-3472-9