Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Avibactam Alone and in Combination with Ceftazidime in Healthy Male Volunteers: Results of Two Randomized, Placebo-Controlled Studies
Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Avibactam Alone and in Combination with Ceftazidime in Healthy Male Volunteers: Results of Two Randomized, Placebo-Controlled Studies
复制标题
DOI：
10.1007/s40261-015-0283-9
复制
发表时间：
2015-05-01
影响因子：
3.2
通讯作者：
Tarral, Antoine
中科院分区：
文献类型：
--
作者：
Merdjan, Henri;Rangaraju, Manickam;Tarral, Antoine
背景与目的阿维巴坦是一种新型非β-内酰胺类β-内酰胺酶抑制剂，对Ambler A、C类和部分D类β-内酰胺酶有效，目前正在临床开发中，与头孢他啶联合治疗严重革兰阴性菌感染。它可以恢复包括头孢他啶在内的一系列β-内酰胺类药物针对产超广谱β-内酰胺酶病原体的体外活性。两项I期研究评估了阿维巴坦单独给药或与头孢他啶联合给药时在健康受试者中的安全性和药代动力学。方法第一项研究（NXL 104 -1001）是一项安慰剂对照、单次剂量递增研究，评估了阿维巴坦50、100、250、500、1000、1500或2000 mg静脉输注30分钟。在7天洗脱期后，250和500 mg给药组的受试者分别接受第二次阿维巴坦给药和伴随头孢他啶1000或2000 mg。第二项研究（NXL 104 -1002）分两部分进行。第1部分评估了阿维巴坦的多次递增剂量。受试者随机接受阿维巴坦500、750或1000 mg每8 h（q8 h）给药，持续5天，或头孢他啶-阿维巴坦2000-500 mg q8 h给药，持续10天。第2部分评估了阿维巴坦单次口服给药（500 mg）后相对于单次30分钟静脉输注（500 mg）的生物利用度。阿维巴坦暴露量通常与剂量成比例增加，多次给药后无蓄积趋势。几乎所有阿维巴坦在前6小时内基本上以原型经尿液排泄。伴随使用头孢他啶不会影响阿维巴坦的安全性和药代动力学特征。阿维巴坦口服给药后的暴露量非常低，为静脉输注后观察到的暴露量的6.2%。结论阿维巴坦在所有给药方案中，无论是单独给药还是与头孢他啶联合给药，总体耐受性良好。在两项研究中，阿维巴坦暴露量均与剂量相关，阿维巴坦药代动力学呈线性，不受头孢他啶影响。
Background and Objective Avibactam is a novel non-beta-lactam beta-lactamase inhibitor effective against Ambler class A, C and some class D beta-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of beta-lactams, including ceftazidime, against extended-spectrum beta-lactamase-producing pathogens. Two phase I studies assessed the safety and pharmacokinetics of avibactam in healthy subjects when administered alone or with ceftazidime.Methods The first study (NXL104-1001) was a placebo-controlled, single-ascending dose study assessing avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg given as a 30-min intravenous infusion. After a 7-day washout, subjects in the 250 and 500 mg dosing groups received a second avibactam dose with concomitant ceftazidime 1000 or 2000 mg, respectively. The second study (NXL104-1002) was performed in two parts. Part 1 assessed multiple-ascending doses of avibactam. Subjects were randomized to receive avibactam 500, 750 or 1000 mg every 8 h (q8 h) over 5 days, or ceftazidime-avibactam 2000-500 mg q8 h over 10 days. Part 2 assessed bioavailability of avibactam after a single oral dose (500 mg) relative to a single 30-min intravenous infusion (500 mg).Results No serious or severe adverse events were reported in either study. Avibactam exposure generally increased proportionally to dose and there was no trend for accumulation after multiple doses. Almost all avibactam was excreted largely unchanged in the urine within the first 6 h. Concomitant ceftazidime did not affect avibactam's safety and pharmacokinetic profile. Avibactam exposure after oral dosing was very low at 6.2 % of that observed after intravenous infusion.Conclusion Avibactam was generally well tolerated across all dosing regimens, when given alone or with ceftazidime. Avibactam exposure was dose related in both studies, and avibactam pharmacokinetics were linear and not affected by ceftazidime.