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

Abstract

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.

• Authors: Timothy Eley, Feng R Luo, Shruti Agrawal, Ashish Sanil, James Manning, Tong Li, Anne Blackwood-Chirchir, Richard Bertz
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 49 Issue 6 Pg. 700-9 (Jun 2009) ISSN: 0091-2700 [Print] England
• PMID: 19395585 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antacids
• Anti-Ulcer Agents
• Histamine H2 Antagonists
• Protein Kinase Inhibitors
• Pyrimidines
• Thiazoles
• Famotidine
• Dasatinib

Topics

• 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, adverse effects, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Thiazoles (administration & dosage, adverse effects, pharmacokinetics)
• Young Adult