Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
Br J Clin Pharmacol. 2023 Jul;89(7):2304-2308. doi: 10.1111/bcp.15743. Epub 2023 Apr 28.
Midostaurin is often prescribed with azole antifungals in patients with leukaemia, either for aspergillosis prophylaxis or treatment. Midostaurin is extensively metabolized by cytochrome (CYP) 3A4. In addition, it inhibits and induces various CYPs at therapeutic concentrations. Thus, midostaurin is associated with a high potential for drug-drug interactions (DDIs), both as a substrate (victim) and as a perpetrator. However, data on midostaurin as a perpetrator of DDIs are scarce, as most pharmacokinetic studies have focused on midostaurin as a victim drug. We report a clinically relevant bidirectional DDI between midostaurin and voriconazole during induction treatment. A 49-year-old woman with acute myeloid leukaemia developed invasive pulmonary aspergillosis after induction chemotherapy. She was treated with voriconazole at standard dosage. Six days after starting midostaurin, she developed visual hallucinations with a concurrent sharp increase in voriconazole blood concentration (C 10.3 mg L , target C 1-5 mg L ). Neurotoxicity was considered to be related to voriconazole overexposure. The concentration of midostaurin was concomitantly six-fold above the average expected level, but without safety issues. Midostaurin was stopped and the dosage of voriconazole was adjusted with therapeutic drug monitoring. The evolution was favourable, with quick resolution and no recurrence of visual hallucinations. To our knowledge, this is the first case suggesting that midostaurin and voriconazole reciprocally inhibit each other's metabolism, leading to increased exposure of both. This case highlights the knowledge gap regarding drug-drug interactions between midostaurin and azole antifungals. Close clinical and therapeutic drug monitoring is advised in such cases.
米哚妥林常用于白血病患者的治疗，联合唑类抗真菌药物（如用于曲霉病的预防或治疗）。米哚妥林主要通过细胞色素（CYP）3A4 广泛代谢。此外，在治疗浓度下，它还能抑制和诱导多种 CYP。因此，米哚妥林具有很高的药物相互作用（DDI）风险，既是底物（受害者），也是诱导剂（肇事者）。然而，由于大多数药代动力学研究都集中在米哚妥林作为受药上，因此关于米哚妥林作为 DDI 诱导剂的数据很少。我们报告了米哚妥林和伏立康唑在诱导治疗期间发生的一种具有临床意义的双向 DDI。一名 49 岁女性因急性髓细胞白血病在诱导化疗后发生侵袭性肺曲霉病。她按标准剂量接受伏立康唑治疗。开始服用米哚妥林 6 天后，她出现了幻视，同时伏立康唑血药浓度（C 10.3mg/L，目标 C 1-5mg/L）急剧升高。认为神经毒性与伏立康唑过量有关。米哚妥林浓度也同时升高至平均预期水平的六倍，但无安全性问题。米哚妥林被停用，同时进行伏立康唑治疗药物监测调整剂量。病情进展良好，幻视迅速缓解且未再复发。据我们所知，这是首例提示米哚妥林和伏立康唑相互抑制对方代谢，导致两者暴露量增加的病例。该病例突出了米哚妥林与唑类抗真菌药物之间相互作用的知识空白。在这种情况下，建议密切进行临床和治疗药物监测。
