Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with β-Lactam Antibiotics in Healthy Subjects
Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with β-Lactam Antibiotics in Healthy Subjects
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DOI：
10.1128/aac.00892-19
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发表时间：
2019-09-01
影响因子：
4.9
通讯作者：
Coleman, Scott
中科院分区：
文献类型：
--
作者：
Eckburg, Paul B.;Lister, Troy;Coleman, Scott
SPR741是一种新型的多粘菌素B衍生物，与多粘菌素B相比，具有最低的内在抗菌活性和减少的非临床肾毒性，它与革兰氏阴性细菌的外膜相互作用，增强联合给药抗生素的渗透。在两项研究中评价了SPR741的安全性、耐受性和药代动力学(PK)。健康成人受试者以及与伙伴抗生素共同给药后的剂量。在单次和多次递增剂量研究中，SPR741或安慰剂作为1h输注，单次剂量为5-800 mg，多次剂量为50-600 mg，每8小时(Q8h)一次，持续14天。在药物-药物相互作用研究中，一次400毫克静脉注射。剂量SPR741单独及与哌拉西林-他唑巴坦、头孢他啶和氨曲南联合应用。SPR741和配对抗生素的PK参数用非隔室分析确定。单次给药后，平均最大血药浓度(C-max)和药时曲线下面积(AUC)呈剂量线性和比例增加。当剂量为100-800毫克时，50%的剂量在服药后的头4小时内从尿液中排出。在多次给药后，第1天的平均半衰期为2.2h，第14天的平均半衰期为14.0h，14d给药至400 mg时未见蓄积迹象。SPR741和伙伴抗生素的PK谱在联合给药时没有变化。SPR741在每天剂量不超过1800毫克时，通常耐受性良好。这些数据支持SPR741进一步的临床开发，用于治疗由耐药细菌引起的严重感染。
SPR741 is a novel polymyxin B derivative, with minimal intrinsic anti-bacterial activity and reduced nonclinical nephrotoxicity compared to levels with polymyxin B, that interacts with the outer membrane of Gram-negative bacteria, enhancing penetration of coadministered antibiotics. The safety, tolerability, and pharmacokinetics (PK) of SPR741 were evaluated in two studies, after single and multiple intravenous (i.v.) doses in healthy adult subjects and after coadministration with partner antibiotics. In the single and multiple ascending-dose study, SPR741 or placebo was administered as a 1-h infusion at single doses of 5 to 800 mg and in multiple doses of 50 to 600 mg every 8 h (q8h) for 14 days. In the drug-drug interaction study, a single 400-mg i.v. dose of SPR741 was administered alone and in combination with piperacillin-tazobactam, ceftazidime, and aztreonam. PK parameters for SPR741 and partner antibiotics were determined using noncompartmental analysis. After single doses, a dose-linear and proportional increase in mean maximum concentration in plasma (C-max) and area under the concentration-time curve (AUC) was observed. At doses of 100 to 800 mg, >50% of the dose was excreted in the urine in the first 4 h postdose. After multiple doses, the mean half-life was 2.2 h on day 1 and up to 14.0 h on day 14, with no evidence of accumulation after 14 days of dosing up to 400 mg. The PK profile of SPR741 and partner antibiotics was unchanged with coadministration. SPR741 was generally well tolerated at doses up to 1,800 mg/day. These data support further clinical development of SPR741 for treating serious infections due to resistant bacteria.