Larfors Gunnar, Andersson Per, Jesson Gérald, Liljebris Charlotta, Brisander Magnus, Lennernäs Hans, Stenke Leif
Unit of Hematology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Xspray, Solna, Sweden.
Eur J Haematol. 2023 Oct;111(4):644-654. doi: 10.1111/ejh.14059. Epub 2023 Jul 28.
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.
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.
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 C nor area under the plasma concentration curve levels in plasma were significantly altered by the PPI co-medication.
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.
达沙替尼及其他酪氨酸激酶抑制剂（TKI）彻底改变了慢性髓性白血病（CML）的治疗方式。然而，作为一种亲脂性弱碱的结晶一水合物，达沙替尼（施达赛®）溶解度很差，导致其吸收依赖于pH值，生物利用度高度可变。因此，与质子泵抑制剂（PPI）联合用药会严重损害达沙替尼的吸收，明确不建议联合使用。XS004是一种新型的达沙替尼口服速释无定形固体分散体（ASD）制剂，在剂量降低30%时与原结晶型达沙替尼生物等效。XS004旨在减轻对胃内pH值的依赖性，从而优化吸收和生物利用度。
我们在真实临床环境中调查了慢性期CML患者中达沙替尼与PPI联合用药的情况，并评估了健康志愿者在联合使用（奥美拉唑）和不联合使用PPI时XS004的血浆药代动力学（PK）。
利用瑞典CML和处方药登记系统，我们确定了676例接受TKI治疗的CML患者；320例（47%）在CML诊断后的某个时间点曾开具PPI处方。在接受达沙替尼治疗的患者中，2年累计PPI联合用药率为24%。有趣的是，接受TKI治疗的CML患者中，联合使用PPI与未联合使用PPI的患者相比，5年总生存率显著更低（79%对94%；风险比3.5；95%置信区间，2.1 - 5.3；p < .0001）。在评估XS004的PK时，联合使用PPI对血浆中的C值或血浆浓度曲线下面积水平均无显著影响。
总之，尽管有警告，但在真实临床环境中，接受达沙替尼治疗的CML患者中PPI联合用药很常见。与原结晶型达沙替尼相比，新型达沙替尼XS004 ASD制剂具有更好的pH值独立性和稳定的生物利用度，从而最大限度地减少了药物相互作用。这可能会提高达沙替尼治疗CML的长期疗效和耐受性。
