Journal
AAPS JOURNAL
Volume 16, Issue 6, Pages 1358-1365Publisher
SPRINGER
DOI: 10.1208/s12248-014-9673-9
Keywords
betaine hydrochloride; dasatinib; drug-drug interactions; pH-dependent solubility; proton pump inhibitors
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Funding
- NIH/NCRR grant [UL1 RR0224131]
- Genentech, Inc.
- NIH Training Grant [T32 GM007175]
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Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib C-max and AUC(0-a) by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib C-max and AUC(0-a) by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions.
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