Relative bioavailability and safety profile of gefitinib administered as a tablet or as a dispersion preparation via drink or nasogastric tube: results of a randomized, open-label, three-period crossover study in healthy volunteers.

摘要

BACKGROUND: Many patients with head and neck cancer have difficulty swallowing tablet formulations of medications, and use of dispersion preparations may be advantageous. OBJECTIVE: The aim of the present study was to determine the relative bioavailability and safety profile of a single dose of gefitinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, when administered as a whole 250-mg tablet or as a dispersion preparation via drink or nasogastric tube in healthy male volunteers. METHODS: This was a Phase 1, randomized, open-label, 3-period crossover study. Plasma samples obtained before dosing to 240 hours after dosing were analyzed for gefitinib using reverse-phase high-performance liquid chromatography with tandem mass-spectrometric detection. The pharmacokinetic parameters of interest included AUC, C(max), and the relative bioavailability of the dispersion via drink or nasogastric tube compared with the standard tablet. RESULTS: Eighteen healthy white male volunteers were enrolled. They had a mean age of 43 years (range, 21-59 years), mean body weight of 85.1 kg (range, 60-101 kg), and mean height of 180.3 cm (range, 171-187 cm). The geometric mean AUC was 2219 ng.h/mL for a single 250-mg dose of gefitinib administered as a whole tablet, 2233 ng.h/mL for the dispersion preparation administered by drink, and 2007 ng.h/mL for the dispersion preparation administered by nasogastric tube. The corresponding values for the geometric mean C(max) were 95.2, 96.3, and 89.9 ng/mL. The gefitinib dispersion preparation administered by drink had a mean bioavailability of 103.8% relative to the whole tablet; the dispersion preparation administered by nasogastric tube had a mean bioavailability of 99.1% relative to the whole tablet. For the drink-tablet and nasogastric tube-tablet comparisons, the estimate-of-treatment ratios for the AUC were a respective 1.006 and 0.928; for the C(max), they were 1.012 and 0.964. There appeared to be no clinically significant differences in absorption or elimination between the preparations. Three volunteers experienced adverse events (AEs) that were considered possibly related to gefitinib (pruritus and dry skin), and 6 volunteers experienced procedure-related AEs (cannula-site reaction and rhinorrhea); these AEs were mild or moderate. No serious AEs were recorded, and no AEs led to withdrawal of any volunteer. CONCLUSIONS: Administration of a 250-mg dose of gefitinib as a dispersion preparation by drink or nasogastric tube achieved a systemic exposure to gefitinib that was consistent with that achieved when gefitinib was administered as a whole tablet. There was no evidence of tolerability problems associated with the routes of administration studied in these healthy volunteers.