Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.
Br J Clin Pharmacol. 2023 Jul;89(7):2309-2315. doi: 10.1111/bcp.15684. Epub 2023 Feb 20.
We present 3 patients diagnosed with rhabdomyolysis 1-6 months after the initiation of concomitant rosuvastatin and ticagrelor medication. A literature review and Food and Drug Administration adverse event reporting system revealed >40 reports of rhabdomyolysis during concomitant ticagrelor and rosuvastatin, including 3 with a fatal outcome. We show that ticagrelor inhibits breast cancer resistance protein-, organic anion transporting polypeptide (OATP) 1B1-, 1B3- and 2B1-mediated transport of rosuvastatin in vitro with half-maximal unbound inhibitory concentrations of 0.36, 4.13, 7.5 and 3.26 μM, respectively. A static drug interaction model predicted that ticagrelor may inhibit intestinal breast cancer resistance protein and thus increase rosuvastatin plasma exposure 2.1-fold, whereas the OATP-mediated hepatic uptake of rosuvastatin should not be inhibited due to relatively low portal ticagrelor concentrations. Taken together, concomitant use of ticagrelor with rosuvastatin may increase the systemic exposure to rosuvastatin and the risk of rosuvastatin-induced rhabdomyolysis. Further studies are warranted to investigate the potential pharmacokinetic interaction between ticagrelor and rosuvastatin in humans.
我们报告了 3 例患者，他们在开始同时使用瑞舒伐他汀和替格瑞洛药物后 1-6 个月被诊断为横纹肌溶解症。文献复习和美国食品和药物管理局不良事件报告系统显示，同时使用替格瑞洛和瑞舒伐他汀期间发生横纹肌溶解症的报告超过 40 例，其中 3 例结局为致命。我们表明，替格瑞洛在体外以半最大无结合抑制浓度 0.36、4.13、7.5 和 3.26 μM 分别抑制乳腺癌耐药蛋白、有机阴离子转运多肽（OATP）1B1、1B3 和 2B1 介导的瑞舒伐他汀转运。静态药物相互作用模型预测，替格瑞洛可能抑制肠道乳腺癌耐药蛋白，从而使瑞舒伐他汀的血浆暴露增加 2.1 倍，而由于门静脉替格瑞洛浓度相对较低，替格瑞洛不应抑制瑞舒伐他汀的肝脏摄取。综上所述，替格瑞洛与瑞舒伐他汀同时使用可能会增加瑞舒伐他汀的全身暴露，增加瑞舒伐他汀引起的横纹肌溶解症的风险。需要进一步研究以探讨替格瑞洛和瑞舒伐他汀在人类体内的潜在药代动力学相互作用。
