Xiaofen Liu1, Yuancheng Chen2, Haijing Yang2, Jian Li3, Jicheng Yu2, Zhenwei Yu4, Guoying Cao2, Xiaojie Wu2, Yu Wang1, Hailan Wu1, Yaxin Fan1, Jingjing Wang2, Jufang Wu2, Yi Jin2, Beining Guo1, Jiali Hu1, Xingchen Bian1, Xin Li1, Jing Zhang5. 1. 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. 2. 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. 3. Biomedicine Discovery Institute and Department of Microbiology, Monash University, 19 Innovation Walk, Victoria 3800, Melbourne, Australia. 4. Sir Run Shaw Hospital, College of Medicine, Zhenjiang University, 3rd East Qingchun Road, Hangzhou 310016, China. 5. 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; Phase I Unit, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: zhangj_fudan@aliyun.com.
Abstract
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Kade D Roberts; Yan Zhu; Mohammad A K Azad; Mei-Ling Han; Jiping Wang; Lynn Wang; Heidi H Yu; Andrew S Horne; Jo-Anne Pinson; David Rudd; Nicolas H Voelcker; Nitin A Patil; Jinxin Zhao; Xukai Jiang; Jing Lu; Ke Chen; Olga Lomovskaya; Scott J Hecker; Philip E Thompson; Roger L Nation; Michael N Dudley; David C Griffith; Tony Velkov; Jian Li Journal: Nat Commun Date: 2022-03-25 Impact factor: 14.919