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Despite warnings, c...
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.
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- Larfors, Gunnar (författare)
- Uppsala universitet,Hematologi
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Andersson, Per (författare)
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Jesson, Gérald (författare)
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Liljebris, Charlotta (författare)
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Brisander, Magnus (författare)
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- Lennernäs, Hans (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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Stenke, Leif (författare)
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(creator_code:org_t)
- 2023
- 2023
- Engelska.
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Ingår i: European Journal of Haematology. - : John Wiley & Sons. - 0902-4441 .- 1600-0609.
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Nyckelord
- CML
- PPI
- XS004
- dasatinib
- drug-drug interactions
- pharmacokinetics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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