Institute of Antibiotics, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission of the People's Republic of China, Shanghai 200040, China; National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China; Phase I Unit, Huashan Hospital, Fudan University, Shanghai 200040, China.
J Infect. 2021 Feb;82(2):207-215. doi: 10.1016/j.jinf.2021.01.006. Epub 2021 Jan 13.
Polymyxin B is a last-line antibiotic for multidrug-resistant gram-negative bacterial infections. However, limited safety and pharmacokinetic information is available. We investigated the safety and pharmacokinetics of intravenous polymyxin B in healthy subjects.
An open-label, single-dose clinical trial was conducted in healthy Chinese subjects. Polymyxin B (sulphate) was administered intravenously at 0.75 or 1.5 mg/kg (n = 10 per dose, 5 males and 5 females) to examine the safety and pharmacokinetics.
One female subject in the 1.5-mg/kg group discontinued due to abdominal pain during administration. The most frequently reported adverse events were perioral paraesthesia, dizziness, and numbness of extremities (7/10 subjects in the 0.75-mg/kg group, all subjects in the 1.5-mg/kg group). All neurotoxicity-related events dissipated without treatment within a maximum of 23 h. Notably, abdominal pain (3/5) and vulvar pruritus (2/5), colpitis (2/5) or abnormal uterine bleeding (1/5) were reported in female subjects receiving the 1.5-mg/kg dose. In the 0.75-mg/kg group, the total clearance, volume of distribution and half-life of polymyxin B were 0.028±0.002 L/h/kg, 0.219±0.023 L/kg and 5.44±0.741 h, respectively; similar values were observed in the 1.5-mg/kg group. Urinary recovery was 3.7 ± 1.1% and 8.1 ± 1.3% in the 0.75- and 1.5-mg/kg groups, respectively. Population pharmacokinetics of polymyxin B was consistent with a three-compartment model. The clearance and distribution of the central compartment were 0.027 L/h/kg and 0.071 L/kg, respectively.
This study is the first to examine the safety and pharmacokinetics of polymyxin B in healthy subjects. Our results highlight that acute toxicity is a dose-limiting factor for intravenous polymyxin B.
多黏菌素 B 是治疗多重耐药革兰氏阴性菌感染的最后一线抗生素。然而，其安全性和药代动力学信息有限。我们研究了健康受试者中静脉内多黏菌素 B 的安全性和药代动力学。
在中国健康受试者中进行了一项开放标签、单剂量临床试验。多黏菌素 B（硫酸盐）以 0.75 或 1.5mg/kg 静脉内给药（每组 10 名，每组 5 名男性和 5 名女性），以检查安全性和药代动力学。
1.5mg/kg 组的 1 名女性受试者因给药期间腹痛而停药。最常报告的不良事件是口周感觉异常、头晕和四肢麻木（0.75mg/kg 组 7/10 例，1.5mg/kg 组所有受试者）。所有与神经毒性相关的事件均在最多 23 小时内无需治疗而消散。值得注意的是，接受 1.5mg/kg 剂量的女性受试者报告了腹痛（3/5）、外阴瘙痒（2/5）、阴道炎（2/5）或异常子宫出血（1/5）。在 0.75mg/kg 组中，多黏菌素 B 的总清除率、分布容积和半衰期分别为 0.028±0.002 L/h/kg、0.219±0.023 L/kg 和 5.44±0.741 h；在 1.5mg/kg 组中观察到相似的值。0.75-和 1.5mg/kg 组的尿回收率分别为 3.7±1.1%和 8.1±1.3%。多黏菌素 B 的群体药代动力学与三房室模型一致。中央室的清除率和分布容积分别为 0.027 L/h/kg 和 0.071 L/kg。
本研究首次研究了健康受试者中多黏菌素 B 的安全性和药代动力学。我们的结果强调，急性毒性是静脉内多黏菌素 B 的剂量限制因素。
