Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Department of Hematology, Azienda Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
Chemotherapy. 2018;63(5):253-256. doi: 10.1159/000494329. Epub 2018 Nov 20.
Invasive fungal disease (IFD) is one of the major causes of morbidity and mortality in immunocompromised patients. Voriconazole (VCZ) and posaconazole (PCZ) remain the most widely used antifungals for the prophylaxis and treatment of IFD. However, VCZ and PCZ are liable for drug-drug interactions and show a pharmacokinetic variability that requires therapeutic drug monitoring (TDM). Isavuconazole (IVZ) is a newest generation triazole antifungal approved for the treatment of invasive aspergillosis (IA) in adult patients and for the treatment of invasive mucormycosis in adult patients for whom treatment with amphotericin B is inappropriate. In clinical trials, IVZ showed linear pharmacokinetics and little or no evidence for interactions with other drugs. There is only modest evidence on IVZ pharmacokinetics and TDM in real-life settings. Here, we report on IVZ pharmacokinetics in a young adult with Ph chromosome-negative acute lymphoblastic leukemia (ALL) who developed a "probable" IA during induction chemotherapy. The patient was initially treated with VCZ, but she developed a severe hepatic toxicity that was associated to the high plasma levels of VCZ. Therefore, VCZ was discontinued and the patient was switched to IVZ. After a loading dose of IVZ, the patient remained on IVZ for 5 months while also receiving standard maintenance chemotherapy for ALL. At day 65 after the start of IVZ, the patient experienced a significant hepatic toxicity; however, no change in IVZ plasma concentrations was observed in the face of a concomitant administration of many other drugs (cancer drugs, antiemetics, other anti-infectives). Hepatic toxicity resolved after discontinuing maintenance chemotherapy but not IVZ. These results show that (i) IVZ plasma concentrations remained stable throughout and were not affected by concomitant ALL therapy, and (ii) there was no relation between IVZ plasma concentration and hepatic toxicity. Thus, in clinical practice IVZ may not require TDM.
侵袭性真菌病 (IFD) 是免疫功能低下患者发病率和死亡率的主要原因之一。伏立康唑 (VCZ) 和泊沙康唑 (PCZ) 仍然是预防和治疗 IFD 最广泛使用的抗真菌药物。然而，VCZ 和 PCZ 容易发生药物相互作用，并表现出需要治疗药物监测 (TDM) 的药代动力学变异性。伊曲康唑 (IVZ) 是一种最新一代三唑类抗真菌药物，已被批准用于治疗成人侵袭性曲霉病 (IA) 和不适合两性霉素 B 治疗的成人侵袭性毛霉病。在临床试验中，IVZ 表现出线性药代动力学特征，几乎没有或没有与其他药物相互作用的证据。在现实环境中，仅有关于 IVZ 药代动力学和 TDM 的少量证据。在这里，我们报告了一名 Ph 染色体阴性急性淋巴细胞白血病 (ALL) 年轻成年患者的 IVZ 药代动力学情况，该患者在诱导化疗期间发生了“疑似”IA。该患者最初接受 VCZ 治疗，但出现严重肝毒性，与 VCZ 血浆水平高有关。因此，停用 VCZ 并改用 IVZ。给予 IVZ 负荷剂量后，患者在接受 ALL 标准维持化疗的同时，继续使用 IVZ 5 个月。在开始使用 IVZ 第 65 天，患者出现明显的肝毒性；然而，在同时使用许多其他药物（癌症药物、止吐药、其他抗感染药物）的情况下，未观察到 IVZ 血浆浓度的变化。停止维持化疗后肝毒性缓解，但未停止 IVZ。这些结果表明：(i) IVZ 血浆浓度在整个治疗过程中保持稳定，不受同时进行的 ALL 治疗的影响；(ii) IVZ 血浆浓度与肝毒性之间没有关系。因此，在临床实践中，IVZ 可能不需要 TDM。
