Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland
Drugs for Neglected Diseases initiative (DNDi), Rio de Janeiro, Brazil.
Antimicrob Agents Chemother. 2021 Mar 18;65(4). doi: 10.1128/AAC.02150-19.
E1224 is a prodrug of ravuconazole (RVZ), an antifungal drug with promising anti- activity, the causative organism of Chagas disease (CD). This study was designed to assess the pharmacokinetics (PK) and safety interactions of benznidazole (BNZ), the drug of choice for treatment of CD, and E1224 in healthy volunteers. This open-label, single-center, sequential, single- and multiple-oral-dose study enrolled 28 healthy male subjects. These subjects received BNZ (2.5 mg/kg) once daily on days 1 and 9 and twice daily from day 12 to day 15 and E1224 once daily from day 4 to day 15 (loading dose of 400 mg for 3 days and maintenance dose of 100 mg for 9 days). The maximum concentration () and area under the concentration curve from zero to infinity for BNZ were comparable, whether BNZ was given alone or with E1224 at steady state, with ratios of geometric means for BNZ-RVZ to BNZ of 0.96 and 0.83 and corresponding 90% confidence intervals (CIs) of 0.91 to 1.10 and 0.80 to 0.87, respectively. However, RVZ and area under the concentration curve from zero to 24 h increased by about 35% when concomitantly administered with BNZ at steady state (ratio of geometric means for RVZ-BNZ/RVZ of 1.31 and 1.36 and corresponding 90% CIs of 1.23 to 1.39 and 1.31 to 1.41, respectively). Both compounds were well tolerated. There were no clinically relevant safety interactions between E1224 and BZN. Given these results, coadministration of RVZ and BNZ should not require any adaptation of E1224 dosing.
E1224 是拉夫康唑（RVZ）的前药，RVZ 是一种具有抗活性的抗真菌药物，也是恰加斯病（CD）的病原体。本研究旨在评估贝那唑（BNZ）和 E1224 在健康志愿者中的药代动力学（PK）和安全性相互作用，BNZ 是治疗 CD 的首选药物。这是一项开放标签、单中心、序贯、单次和多次口服剂量研究，共纳入 28 名健康男性受试者。这些受试者在第 1 天和第 9 天每天接受 BNZ（2.5mg/kg）一次，从第 12 天到第 15 天每天两次，从第 4 天到第 15 天每天一次 E1224（前 3 天 400mg 负荷剂量，后 9 天 100mg 维持剂量）。无论 BNZ 单独使用还是与 E1224 在稳态时联合使用，BNZ 的最大浓度（）和从 0 到无穷大的浓度曲线下面积均相当，BNZ-RVZ 与 BNZ 的几何均数比值为 0.96 和 0.83，相应的 90%置信区间（CI）分别为 0.91 至 1.10 和 0.80 至 0.87。然而，当 BNZ 在稳态时同时给药时，RVZ 和从 0 到 24 小时的浓度曲线下面积增加了约 35%（RVZ-BNZ/RVZ 的几何均数比值为 1.31 和 1.36，相应的 90%CI 分别为 1.23 至 1.39 和 1.31 至 1.41）。两种化合物均耐受良好。E1224 和 BZN 之间没有临床相关的安全性相互作用。鉴于这些结果，RVZ 和 BNZ 的联合给药不应需要调整 E1224 的剂量。
