Impact of Proton Pump Inhibitor (PPI) Comedication on Chronic Myeloid Leukemia (CML) Patients Treated with Dasatinib

Chronic myeloid leukemia (CML) has seen significant advancements with the introduction of tyrosine kinase inhibitors (TKIs), such as dasatinib (Sprycel®). However, dasatinib's bioavailability is highly dependent on gastric pH, which poses challenges for patients co-medicated with proton pump inhibitors (PPIs). PPIs, such as omeprazole, reduce gastric acidity, thus decreasing the absorption of dasatinib. This interaction results in a significant reduction in dasatinib plasma exposure, often by more than 40%, making the coadministration of dasatinib and PPIs a clinical challenge. Regulatory bodies, including the U.S. FDA, recommend against this combination due to concerns about reduced efficacy.

A study using data from the Swedish CML and Prescribed Drug Registries analyzed the prevalence and effects of PPI-TKI comedication in a real-world setting. Among 676 TKI-treated CML patients, 320 (47%) had been prescribed PPIs after their diagnosis, reflecting a high prevalence of such comedication. Specifically, 24% of dasatinib-treated patients had received PPI prescriptions within two years of starting treatment. Given the widespread use of over-the-counter (OTC) PPIs in Sweden, the actual prevalence of PPI use among CML patients is likely higher.

Critically, the study revealed that TKI-treated CML patients who were co-medicated with PPIs had worse survival outcomes. The five-year overall survival (OS) for patients without PPI comedication was 94%, while for those with PPI comedication, it dropped to 79%. These findings suggest that PPI comedication negatively impacts the effectiveness of dasatinib and contributes to poorer clinical outcomes in CML patients.

XS004: A Novel Dasatinib Formulation with Reduced pH Dependency

Given the challenges posed by PPI-TKI interactions, XS004, a new formulation of dasatinib, has been developed. XS004 uses an amorphous solid dispersion (ASD) technology, designed to increase dasatinib solubility in a broader pH range (acidic to neutral). This reduces its dependency on gastric acidity, thus mitigating the adverse effects of PPI comedication. A pharmacokinetic (PK) study conducted with 16 healthy volunteers showed that the bioavailability of XS004 was not significantly affected by the concurrent administration of omeprazole. Plasma concentration parameters such as Cmax and AUC remained within acceptable ranges (80%-125%) whether XS004 was taken alone or with omeprazole.

The improved pH independence of XS004 represents a promising solution for CML patients requiring both dasatinib and PPI treatment. With this new formulation, XS004 can potentially maintain consistent plasma concentrations even when co-medicated with PPIs, reducing variability in drug absorption and ensuring better therapeutic efficacy.

The high prevalence of PPI comedication among CML patients, despite warnings, underscores the need for alternative therapeutic approaches. The association between PPI use and reduced survival in TKI-treated patients highlights the importance of managing drug-drug interactions. XS004 offers an innovative solution, providing reduced pH dependency and minimizing the impact of PPIs on dasatinib's efficacy. By improving bioavailability and tolerability, XS004 has the potential to enhance long-term outcomes for CML patients in need of PPI medication​.

References

Larfors, Gunnar & Andersson, Per & Jesson, Gérald & Liljebris, Charlotta & Brisander, Magnus & Lennernäs, Hans & Stenke, Leif. (2023). 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. European Journal of Haematology. 111. 10.1111/ejh.14059.