Comedication of Proton Pump Inhibitors and Dasatinib Is Common in CML but XS004, a Novel Amorphous Solid Dispersion Formulation of Dasatinib, Provides Improved Uptake and Low pH-Dependency, Minimizing Unwanted Drug-Drug Interactions

Dasatinib (Sprycel^®), together with other tyrosine kinase inhibitors (TKI), has profoundly improved the prognosis of patients with chronic myeloid leukemia (CML). However, as a lipophilic, poorly soluble, weakly basic, orally applied drug, the bioavailability of dasatinib is highly pH-dependent, with significantly reduced plasma concentrations at higher gastric pH. Comedication with proton pump inhibitors (PPI) such as omeprazole, thus provides a clinical challenge, decreasing dasatinib plasma exposure by more than 40%. Consequently, dasatinib and PPI comedication is cautioned against by the FDA (US).

Here we studied TKI-PPI comedication by investigating the prevalence and outcome of such treatments in CML patients in a real-world setting and by assessing the influence of PPI-comedication on the plasma pharmacokinetics of XS004-dasatinib (XS004, Xspray Pharma, Solna, Sweden), a novel immediate release and amorphous solid dispersion (ASD) formulation of dasatinib.

Using the Swedish CML- and Prescribed Drug-Registries we identified 722 chronic phase CML-patients, of which 676 (93.6%) had received TKI treatment. We observed that 302 (45%) of these had also been prescribed PPI at some point after CML diagnosis. Among patients given dasatinib, the two-year cumulative prescribed comedication with PPI was 24%. With longer follow-up and given the fact that unprescribed but difficult to quantify over-the-counter usage of PPI is common in Sweden, the proportion of patients with such comedication is likely to be considerably larger.

Interestingly, the estimated 5-year survival was lower for TKI-treated CML patients with vs. without PPI comedication (79% vs. 94%; total 5-years survival of TKI-treated CML patients: 88%). This corresponds to a significantly increased crude hazard ratio (HR) of death of 3.5 (95% CI, 2.1-5.3, p<0.0001) and a HR of 3.1 (95% CI, 2.0-4.7, p<0.0001) after adjusting for age, sex, year of diagnosis, and comorbidity index.

Further, we assessed the pharmacokinetics of XS004, given alone or together with omeprazole, to sixteen healthy volunteers in a cross-over study design. XS004 is produced with the HyNap™ technology allowing for an ASD-formulation of dasatinib and is designed to increase solubility of the active drug substance in slightly acidic to neutral gastrointestinal pH conditions, thereby reducing gastric pH dependency and promoting optimized absorption and bioavailability of the drug. XS004 has demonstrated improved bioavailability and reduced intra- and inter-individual variability when compared to the original, non-ASD formulated dasatinib (Sprycel^®). As shown in Table 1, describing plasma pharmacokinetics of XS004 administered as a single drug or together with omeprazole, neither C_max nor plasma AUC values of XS004 were significantly altered by the PPI comedication. This contrasts with previous studies describing clear reductions of non-ASD formulated dasatinib plasma AUC after comedication with PPI.

We conclude that, despite warnings, co-medication with PPI is common among dasatinib-treated CML patients in a real-world setting. Our data suggest that PPI-comedication to TKI can negatively influence the survival of CML patients, although covariant factors may be present. The plasma pharmacokinetics of XS004 dasatinib was, in contrast to the original non-ASD, pH-sensitive dasatinib formulation, not significantly affected by comedication with omeprazole. In the clinic, with its low pH-dependency and augmented intestinal absorption, XS004 dasatinib can provide an improved option for safely administering the often-needed comedication with PPIs, potentially improving long-term efficacy and tolerability of dasatinib in CML.