Novartis Pharma AG, CH-4002, Basel, Switzerland.
Cancer Chemother Pharmacol. 2022 Jul;90(1):19-27. doi: 10.1007/s00280-022-04448-w. Epub 2022 Jun 25.
Midostaurin, approved for the treatment of newly diagnosed, FLT3-mutated acute myeloid leukemia (AML), is metabolized by cytochrome P450 3A4 (CYP3A4). Midostaurin with concomitant strong CYP3A4 inhibitors use (e.g., antifungal azoles) may result in drug-drug interactions. This post hoc analysis of RATIFY phase 3 study data evaluated effects of strong CYP3A4 inhibitor use on the exposure and safety of midostaurin.
Trough concentrations were used to assess midostaurin and metabolite exposure in the presence and absence of strong CYP3A4 inhibitors. Adverse event (AE) frequency was assessed in patients who received concomitant strong CYP3A4 inhibitors vs those who did not. Time to first clinically notable AE (CNAE) was also assessed in patients with high midostaurin plasma exposure vs those of matched placebo controls.
Use of concomitant strong CYP3A4 inhibitors was most frequent during the induction phase (60.8%). A 1.44-fold increase in midostaurin plasma exposure was observed in patients with concomitant strong CYP3A4 inhibitor use vs those without. Midostaurin-treated patients who received concomitant strong CYP3A4 inhibitors experienced grade 3/4 infection-related AEs more frequently vs those who did not. Patients with high levels of midostaurin exposure had a shorter median time to first grade 3/4 CNAE vs placebo controls (36 vs 41 days, respectively; P = .012).
Although concomitantly administered strong CYP3A4 inhibitors increased midostaurin exposure 1.44-fold, no clinically relevant differences in safety were noted. Midostaurin dose adjustment is not necessary with concomitant strong CYP3A4 inhibitors in patients with FLT3-mutated AML; however, caution is advised, and patients should be closely monitored.
米哚妥林获批用于治疗新诊断的 FLT3 突变型急性髓系白血病（AML），其代谢依赖细胞色素 P450 3A4（CYP3A4）。米哚妥林与强 CYP3A4 抑制剂同时使用（如抗真菌唑类药物）可能导致药物相互作用。本研究对 RATIFY Ⅲ期研究数据进行了事后分析，评估了强 CYP3A4 抑制剂的使用对米哚妥林暴露和安全性的影响。
采用谷浓度评估强 CYP3A4 抑制剂存在和不存在时米哚妥林及其代谢物的暴露情况。评估接受强 CYP3A4 抑制剂与未接受强 CYP3A4 抑制剂的患者不良反应（AE）的发生频率。在高米哚妥林血浆暴露患者与匹配安慰剂对照患者中，也评估了首次出现临床显著不良事件（CNAE）的时间。
诱导期最常同时使用强 CYP3A4 抑制剂（60.8%）。与未同时使用强 CYP3A4 抑制剂的患者相比，同时使用强 CYP3A4 抑制剂的患者米哚妥林血浆暴露增加了 1.44 倍。与未同时使用强 CYP3A4 抑制剂的患者相比，接受强 CYP3A4 抑制剂的米哚妥林治疗患者更常发生 3/4 级感染相关 AE。高米哚妥林暴露患者首次发生 3/4 级 CNAE 的中位时间短于安慰剂对照患者（分别为 36 天和 41 天；P = .012）。
尽管同时给予强 CYP3A4 抑制剂使米哚妥林暴露增加了 1.44 倍，但未观察到安全性方面的临床相关差异。在 FLT3 突变型 AML 患者中，与强 CYP3A4 抑制剂同时使用时无需调整米哚妥林剂量；但应谨慎，并密切监测患者。
