We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Despite warnings, co‐medication with proton pump inhibitors and dasatinib is common in chronic myeloid leukemia, but XS004, a novel oral dasatinib formulation, provides reduced pH‐dependence, minimizing undesirable drug–drug interactions
- Authors
Larfors, Gunnar; Andersson, Per; Jesson, Gérald; Liljebris, Charlotta; Brisander, Magnus; Lennernäs, Hans; Stenke, Leif
- Abstract
Background: Dasatinib and other tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML). However, as a lipophilic weak base, crystalline monohydrate, dasatinib (Sprycel®) is poorly soluble, rendering a pH‐dependent absorption and a highly variable bioavailability. Thus, co‐medication with proton pump inhibitors (PPI) profoundly impairs dasatinib uptake and is clearly recommended against. XS004 is a novel oral immediate release and amorphous solid dispersion (ASD) formulation of dasatinib and is bioequivalent to the original crystalline dasatinib at 30% lower dosages. XS004 is designed to mitigate gastric pH dependency, thus optimizing absorption and bioavailability. Methods: We investigated the prevalence of dasatinib and PPI co‐medication among chronic‐phase CML patients in a real‐world setting and assessed the plasma pharmacokinetics (PK) of XS004 with and without PPI co‐medication (omeprazole) in healthy volunteers. Results: Using the Swedish CML and Prescribed Drug Registers, we identified 676 TKI‐treated CML patients; 320 (47%) had been prescribed PPI at some point after CML diagnosis. Among dasatinib‐treated patients, the 2‐year cumulative PPI co‐medication was 24%. Interestingly, the 5‐year overall survival was significantly lower for TKI‐treated CML patients with versus without PPI co‐medication (79% vs. 94%; hazard ratio 3.5; 95% confidence interval, 2.1–5.3; p <.0001). When assessing PK of XS004, neither Cmax nor area under the plasma concentration curve levels in plasma were significantly altered by the PPI co‐medication. Conclusion: In conclusion, despite warnings, PPI co‐medication is common among dasatinib‐treated CML patients in a real‐world setting. The new XS004 ASD formulation of dasatinib provided, in contrast to original crystalline dasatinib, superior pH independence with stable bioavailability, thereby minimizing drug–drug interactions. This may improve the long‐term efficacy and tolerability of dasatinib in CML.
- Subjects
DASATINIB; PROTON pump inhibitors; CHRONIC myeloid leukemia; DRUG interactions; PROTEIN-tyrosine kinase inhibitors; AMORPHOUS substances
- Publication
European Journal of Haematology, 2023, Vol 111, Issue 4, p644
- ISSN
0902-4441
- Publication type
Article
- DOI
10.1111/ejh.14059