Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability

• Published in: JOURNAL OF CLINICAL ONCOLOGY Vol. 42; no. 16_suppl; p. 6561
• Main Authors: Dahlén, Torsten, Larfors, Gunnar, Lennernäs, Hans, Liljebris, Charlotta, Von Euler, Mikael, Brisander, Magnus, Andersson, Per, Stenke, Leif
• Format: Journal Article Conference Proceeding
• Language: English
• Published: 01.06.2024
• Subjects: Medicin och hälsovetenskap
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2024.42.16_suppl.6561

6561 Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, C max and AUC 0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]