Kovanda Laura L, Marty Francisco M, Maertens Johan, Desai Amit V, Lademacher Christopher, Engelhardt Marc, Lu Qiaoyang, Hope William W
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.
Antimicrob Agents Chemother. 2017 May 24;61(6). doi: 10.1128/AAC.00101-17. Print 2017 Jun.
Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUC]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate.
硫酸艾沙康唑是艾沙康唑的水溶性前药。群体分析表明，在不同患者群体中，其药代动力学（PK）行为相对可预测。我们使用群体PK模型评估了黏膜炎对口服艾沙康唑暴露量的影响。本研究纳入了在两项艾沙康唑3期试验中接受治疗的患者，SECURE试验用于治疗侵袭性曲霉病（IA）和其他丝状真菌，VITAL试验用于治疗毛霉病、由其他罕见真菌引起的侵袭性真菌病（IFD）或IA以及肾功能损害患者。各研究点的研究者报告了黏膜炎情况，并评估了其对口服生物利用度的影响。口服制剂的使用由研究者自行决定。在使用硫酸艾沙康唑期间采集了血浆样本的患者被纳入群体PK模型的构建。在纳入的250例患者中，有56例在口服艾沙康唑治疗开始时或作为不良事件出现黏膜炎。口服生物利用度水平相当，分别为98.3%和99.8%。根据均值或中位数参数估计计算的平均药物暴露量（平均曲线下面积[AUC]）在有黏膜炎和无黏膜炎的患者之间没有差异。接受口服治疗的有黏膜炎和无黏膜炎患者的死亡率和总体临床反应相似。我们发现，尽管口服生物利用度存在差异，但在能够服用硫酸艾沙康唑的这部分黏膜炎患者中，艾沙康唑的暴露量和临床结果与无黏膜炎患者相当。因此，黏膜炎可能并不妨碍使用硫酸艾沙康唑的口服制剂。
