目标:Midostaurin,批准用于治疗FLT-3突变的急性髓细胞性白血病和晚期系统性肥大细胞增多症,被细胞色素P450(CYP)3A4代谢为两种主要代谢产物,并且可以抑制和/或诱导CYP3A,CYP2B6和CYP2C8。两项研究调查了midostaurin对健康参与者的CYP底物药物和口服避孕药的影响。
方法:使用前哨给药对参与者的安全性,在25天(研究1)或24天(研究2)每天两次给药50mg后,midostaurin在稳态下的作用对CYP底物进行了评估,咪达唑仑(CYP3A4),安非他酮(CYP2B6),研究1中的吡格列酮(CYP2C8)和研究2中的单相口服避孕药(含炔雌醇[EES]和左炔诺孕酮[LVG])。
结果:在研究1中,midostaurin导致咪达唑仑峰值血浆浓度(Cmax)增加10%,总暴露量(AUC)减少3-4%。安非他酮显示出Cmax降低55%和AUC降低48-49%。吡格列酮显示Cmax降低10%和AUC降低6%。在研究2中,midostaurin导致EES的Cmax增加26%和AUC增加7-10%;以及LVG的Cmax增加19%和AUC增加29-42%。Midostaurin50mg每天两次,持续28天,可确保在CYP底物药物或口服避孕药给药时达到Midostaurin和活性代谢物的稳态浓度。没有报告安全问题。
结论:Midostaurin既不抑制也不诱导CYP3A4和CYP2C8,而微弱诱导CYP2B6。Midostaurin在稳态下对激素避孕药没有临床相关的PK相互作用。所有治疗均耐受良好。
OBJECTIVE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of
midostaurin on CYP substrate drugs and oral contraceptives in healthy participants.
METHODS: Using sentinel dosing for participants\' safety, the effects of
midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2.
RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG.
Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of
midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported.
CONCLUSIONS: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6.
Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.