作为靶向异柠檬酸脱氢酶2(IDH2)突变蛋白的选择性和有效的抑制剂,enasidenib于2017年获得美国食品和药物管理局(FDA)批准用于患有IDH2突变的急性髓系白血病(AML)成年患者.体外研究表明,依纳西地尼影响各种药物代谢酶和转运蛋白。目前的调查旨在评估依纳西地尼对CYP底物的药代动力学(PKs),包括右美沙芬(CYP2D6探针药物),氟比洛芬(CYP2C9探针药物),咪达唑仑(CYP3A4探针药物),奥美拉唑(CYP2C19探针药物),和吡格列酮(CYP2C8探针药物),AML或骨髓增生异常综合征患者。结果表明,依纳西地尼(100毫克,每天一次)持续28天,右美沙芬的PK参数AUC(0-∞)和Cmax增加了1.37倍(90%置信区间(CI):0.96,1.96)和1.24倍(90%CI:0.94,1.65),分别,与单独的右美沙芬相比。对于氟比洛芬,这些参数增加了1.14(90CI:1.01,1.29)和0.97(90%CI0.86,1.08)倍,分别,与单独的氟比洛芬相比。相反,咪达唑仑降低至0.57(90%CI0.34,0.97)和0.77(90%CI0.39,1.53)倍,分别,与单独的咪达唑仑相比。奥美拉唑的参数增加了1.86(90%CI:1.33,2.60)和1.47(0.93,2.31)倍,分别,与单独的奥美拉唑相比,而吡格列酮的指数下降到0.80(90%CI:0.62,1.03)和0.87(90%CI:0.65,1.16)倍,分别,与单独的吡格列酮相比。这些发现为剂量建议提供了有价值的见解,这些剂量建议涉及与依纳西地尼同时给药时充当CYP2D6,CYP2C9,CYP3A4,CYP2C19和CYP2C8底物的药物。
As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug),
omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for
omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to
omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.