Association of concurrent acid-suppression therapy with survival outcomes and adverse event incidence in oncology patients receiving erlotinib

PURPOSE: Acid-suppression therapy is known to decrease the systemic exposure of erlotinib. The erlotinib prescribing information also recommends staggering dosing with a histamine-2 receptor antagonist (H(2)RA) and avoiding concurrent use of a proton-pump inhibitor (PPI). This retrospective analysis evaluated the frequency of concurrent acid-suppression therapy in oncology patients receiving erlotinib and its association with outcomes. METHODS: All patients prescribed erlotinib within UC San Diego Health System between February 26, 2011 and February 28, 2014 were assessed for eligibility, and for survival outcomes and adverse events. RESULTS: Of the 76 patients in the analysis, 24 were prescribed both a PPI and an H(2)RA with erlotinib therapy (31.6%). The two patient groups, with (n=24) and without PPI/H(2)RA (n=52), were similar in clinical characteristics and erlotinib dose. One patient received an H(2)RA therapy alone and was excluded from the analysis; no one received PPI therapy alone. Patients receiving erlotinib alone had a longer median progression-free survival (PFS) compared to patients with concurrent PPI/H(2)RA therapy (11.0 months vs. 5.3 months; P=0.029). Overall survival (OS) and incidence of rash and/or diarrhea did not correlate with use of acid-suppression therapy. CONCLUSION: Nearly one-third of subjects received acid-suppression therapy. Patients treated with erlotinib and PPI/H(2)RA therapy had shorter PFS, but similar OS and adverse event profile compared to those who did not receive acid-suppression

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

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