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

Abstract

Abstract. 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-∞ by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib C max and AUC 0-∞ 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. KEY WORDS: betaine hydrochloride; dasatinib; drug-drug interactions; pH-dependent solubility; proton pump inhibitors.

Pretreatment With Rifampicin and Tyrosine Kinase Inhibitor Dasatinib Potentiates the Inhibitory Effects Toward OATP1B1- and OATP1B3-Mediated Transport

“…The virtual populations of healthy Caucasian subjects had an age range from 20 to 50 years, and 50% of the population were female. Dose, dosing interval, and dosing duration of dasatinib, rifampicin and pravastatin were similar to those used in the reported clinical studies 35,36 . CsA was used as a calibrator compound for OATP-mediated DDIs as an in vitro - to - in vivo extrapolation of OATP transport in Caucasians could be established 3 .…”

In vitro dissolution methodology, mini-Gastrointestinal Simulator (mGIS), predicts better in vivo dissolution of a weak base drug, dasatinib

“…The predicted pharmacokinetic parameters of dasatinib with the elevated gastric pHs, 4.0 and 6.0, with mg IS exhibited diminished C max (90-98% reduction) and AUC (41-89% reduction) compared to the pharmacokinetic parameter of gastric pH 1.2 suggesting that the elevated gastric pH range of 4.0-6.0 would significantly reduce the drug dissolution and, as a result, the oral absorption of dasatinib. Yago and colleagues demonstrated a 94% and 83% reduction of C max and AUC, respectively, from the mean elevated gastric pH 4.1 compared to the base range of gastric pH 0.5-1.8, while the other demonstrated 60% reduction of AUC of dasatinib absorption with elevated gastric pH (Eley et al, 2009;Yago et al, 2014). The predicted dasatinib absorption with dissolution results by USP apparatus II (pH6.5 SIF) exhibited much lower C max and AUC and did not capture the dissolution changes affected by the change of gastric pH because USP dissolution apparatus II is a fixed pH dissolution methodology.…”

“…These orally administered anticancer drugs exhibit pH-dependent solubility and are often categorized as BCS class II weak base drugs (BCS class IIb) (Budha et al, 2012). With their physicochemical characteristics, the oral bioavailability of those drugs has been reported to be reduced with the co-administration of acid-reducing agents, which cancer patients often take for palliation of the gastroesophageal reflux, and gastritis (Budha et al, 2013(Budha et al, , 2012Duong and Leung, 2011;Kletzl et al, 2015;Yago et al, 2014;Yin et al, 2013). The drug-drug interactions (DDIs) due to elevated gastric pH by co-administration of proton-pump inhibitors (PPIs) have a huge effect on drug dissolution, that can subsequently impact the drug absorption.…”

Pharmacokinetics and Absorption of the Anticancer Agents Dasatinib and GDC-0941 under Various Gastric Conditions in Dogs – Reversing the Effect of Elevated Gastric pH with Betaine HCl

“…8 The coadministration of betaine HCl was also recently shown to improve dasatinib absorption in volunteers receiving the PPI rabeprazole. 26 It is however important to ensure that the increase in gastric acidity remains transient and does not abrogate the therapeutic benefit of ARA in patients.…”

“…For dasatinib, the major impact observed with higher gastric pH and the success of the reacidification approach tested in dogs are consistent with results obtained in human. 20,26 It will be valuable to investigate and confirm whether the results obtained in dogs with GDC-0941 were also predictive of the behavior of this compound under low gastric acidity in human. …”