Pharmacokinetics and Safety of Single and Multiple Doses of ACHN-490 Injection Administered Intravenously in Healthy Subjects
Pharmacokinetics and Safety of Single and Multiple Doses of ACHN-490 Injection Administered Intravenously in Healthy Subjects
复制标题
DOI：
10.1128/aac.00624-11
复制
发表时间：
2011-12-01
影响因子：
4.9
通讯作者：
Bruss, Jon B.
中科院分区：
文献类型：
--
作者：
Cass, Robert T.;Brooks, Carter D.;Bruss, Jon B.
ACHN-490是一种氨基糖苷类抗生素，具有抗多重耐药病原体的活性，包括对目前使用的氨基糖苷类抗生素耐药的病原体。两项随机、双盲、安慰剂对照临床研究在健康受试者中研究了ACHN-490注射液的药代动力学（PK）、安全性和耐受性。研究1采用平行组设计，单次给药（SD）和多次给药（MD）递增。研究2探索了第一项研究中耐受的最高剂量的更长持续时间。受试者被随机分配接受ACHN-490注射液或安慰剂10分钟静脉输注。研究1入组了39例受试者（30例活性药物组和9例安慰剂组），包括1 mg/kg体重单次给药，随后分别给药10、10、5和3天的4、7、11和15 mg/kg递增SD和MD队列。研究2入组了8例受试者（6例活性药物和2例安慰剂），接受15 mg/kg给药5天。根据不良事件（AE）报告、标准临床实验室程序以及肾、耳蜗和前庭功能检测评估安全性。ACHN-490表现出线性和剂量比例性PK，评估的PK参数在研究间一致。15 mg/kg剂量在5天内重复给药后未蓄积。15 mg/kg第5天给药的0 - 24 h浓度-时间曲线下面积（AUC（0-24））、血清药物最大浓度（C-max）、半衰期（t（1/2））、清除率和稳态分布容积（V-ss）的平均稳态（+/-标准差）为239 +/- 45 h。mg/升、113 +/-17 mg/升、3 +/-0.3 h、1.1 +/-0.1 ml/min/kg和0.24 +/-0.04升/kg。AE为轻度至中度，并迅速消退。未观察到肾毒性或耳毒性证据。
ACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects (6 active and 2 placebo) who received 15 mg/kg for 5 days. Safety was assessed from adverse event (AE) reporting, standard clinical laboratory procedures, and testing for renal, cochlear, and vestibular function. ACHN-490 exhibited linear and dose-proportional PK, with agreement between the studies for PK parameters assessed. The 15-mg/kg dose did not accumulate with repeated dosing over 5 days. Mean steady-state (+/- standard deviation) area under the concentration-time curve from 0 to 24 h (AUC(0-24)), maximum concentration of drug in serum (C-max), half-life (t(1/2)), clearance, and volume of distribution at steady state (V-ss) for the 15-mg/kg, day 5 dose were 239 +/- 45 h . mg/liter, 113 +/- 17 mg/liter, 3 +/- 0.3 h, 1.1 +/- 0.1 ml/min/kg, and 0.24 +/- 0.04 liters/kg, respectively. AEs were mild to moderate and rapidly resolved. No evidence of nephrotoxicity or ototoxicity was observed.