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.

The Use of Betaine HCl to Enhance Dasatinib Absorption in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria

“…The effects of elevated gastric pH on drug absorption of weakly basic drugs due to concomitant administration of ARAs have been widely studied, and it is well known that significant reductions in systemic concentrations and drug exposures are observed as a result (4)(5)(6). Interestingly, in the current study when subjects were administered with dasatinib after rabeprazole pretreatment (treatment B), the reductions in dasatinib C max and AUC were far greater than previously reported in studies using famotidine (5) or omeprazole (22), Table III Data from one subject was excluded from analysis as the terminal phase of dasatinib pharmacokinetics could not be estimated in which reductions of approximately 60% were seen.…”

“…For many orally administered, weakly basic compounds with pH-dependent solubility, coadministration with ARAs has been shown to lower drug solubility at the time of their administration, thereby reducing systemic concentrations and drug exposure (4)(5)(6). Although the severity of this interaction can depend on the therapeutic window of the drug and on the degree to which drug solubility is pH-dependent, small molecule anticancer agents are at risk for having much lower oral bioavailability and subtherapeutic concentrations when coadministered with ARAs (7).…”

“…Dasatinib is weakly basic in nature and exhibits a pH-dependent solubility, becoming practically insoluble in water above pH 6 (solubility <0.008 mg/mL) (9). In a study published in 2009, dasatinib area under the concentration versus time curve (AUC) and maximum plasma concentration (C max ) were reduced by approximately 60% when given following a single oral dose of famotidine (40 mg), an H 2 -RA, administered 10 h prior (5). Although it has been proposed to further separate the time the two drugs are administered as a way to possibly prevent this interaction, a dose timing strategy might not always be clinically feasible.…”

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

“…128 Interestingly, coadministration of a high-fat meal has been found to reduce the AUC and C max of crizotinib by ß14%, 128 but its product information indicates that it may be taken without regard to food. 137 Histamine H2-receptor antagonists (H2RAs) significantly decrease the absorption of dastanib, 138,139 and it is estimated that PPIs may have a more profound effect. 138 Consequently, H2RAs, antacids, or PPIs should not be administered concomitantly with dasatinib.…”

“…137 Histamine H2-receptor antagonists (H2RAs) significantly decrease the absorption of dastanib, 138,139 and it is estimated that PPIs may have a more profound effect. 138 Consequently, H2RAs, antacids, or PPIs should not be administered concomitantly with dasatinib. 140 Dasatinib's bioavailability increases when administered with food, but not to a clinically relevant extent.…”