title: 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.affiliation: Bristol-Myers Squibb Company, Mailstop: 8A-1.19, 311 Pennington-Rocky Hill Road, Hopewell, NJ 08534, USA. timothy.eley@bms.com
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.forename: Feng R
authors.initials: FR
authors.lastname: Luo
authors.forename: Shruti
authors.initials: S
authors.lastname: Agrawal
authors.forename: Ashish
authors.initials: A
authors.lastname: Sanil
authors.forename: James
authors.initials: J
authors.lastname: Manning
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.forename: Anne
authors.initials: A
authors.lastname: Blackwood-Chirchir
authors.forename: Richard
authors.initials: R
authors.lastname: Bertz
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000863:Antacids / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001682:Biological Availability; D018592:Cross-Over Studies; D000069439:Dasatinib; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D015738:Famotidine / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000863:Antacids; D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D015738:Famotidine; D000069439:Dasatinib