Phase I study of the effect of gastric acid pH modulators on the bioavailability of oral dasatinib in healthy subjects

• Published in: Journal of clinical pharmacology Vol. 49; no. 6; p. 700
• Main Authors: Eley, Timothy, Luo, Feng R, Agrawal, Shruti, Sanil, Ashish, Manning, James, Li, Tong, Blackwood-Chirchir, Anne, Bertz, Richard
• Format: Journal Article
• Language: English
• Published: England 01.06.2009
• Subjects: Administration, Oral; Adolescent; Adult; Antacids - pharmacology; Anti-Ulcer Agents - pharmacology; Biological Availability; Cross-Over Studies; Dasatinib; Drug Interactions; Drug Therapy, Combination; Famotidine - pharmacology; Histamine H2 Antagonists - pharmacology; Humans; Male; Middle Aged; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Thiazoles - administration & dosage; Thiazoles - adverse effects; Thiazoles - pharmacokinetics; Young Adult
• ISSN: 0091-2700
• DOI: 10.1177/0091270009333854

Dasatinib is a tyrosine kinase inhibitor (including BCR-ABL and the SRC family) that is effective in patients with chronic myeloid leukemia. Dasatinib has pH-dependent solubility and is bioavailable as an oral formulation. The effect of gastric pH modifiers on dasatinib pharmacokinetics is evaluated in an open-label, randomized, 3-period, 3-treatment crossover study. Twenty-four healthy subjects receive treatment A (2 doses of dasatinib 50 mg separated by 12 hours), treatment B (famotidine 40 mg given 2 hours after dasatinib 50 mg and 10 hours before another dose of dasatinib 50 mg), and treatment C (30 mL of an antacid containing aluminum/magnesium hydroxides given 2 hours before dasatinib 50 mg and concomitantly with dasatinib 50 mg 12 hours after the previous dasatinib dose); a 7-day washout separates each treatment period. When famotidine is administered 2 hours after dasatinib, dasatinib exposure is similar to dasatinib administered alone. However, dasatinib exposure is reduced by approximately 60% when famotidine is administered 10 hours before dasatinib dosing. In contrast, dasatinib exposure is unchanged when antacid (Maalox) is administered 2 hours before dasatinib; but when the antacid is coadministered with dasatinib, dasatinib exposure is reduced by approximately 55% to 58%. This indicates that H(2)-receptor antagonists should not be coadministered with dasatinib. Dasatinib may be administered with acid-neutralizing antacids if the doses are temporally separated by at least 2 hours.