Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects |
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Authors: | Xiaofen Liu Yuancheng Chen Haijing Yang Jian Li Jicheng Yu Zhenwei Yu Guoying Cao Xiaojie Wu Yu Wang Hailan Wu Yaxin Fan Jingjing Wang Jufang Wu Yi Jin Beining Guo Jiali Hu Xingchen Bian Xin Li Jing Zhang |
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Institution: | 1. Institute of Antibiotics, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China;2. Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission of the People''s Republic of China, Shanghai 200040, China;3. National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China;4. Phase I Unit, Huashan Hospital, Fudan University, Shanghai 200040, China;5. Biomedicine Discovery Institute and Department of Microbiology, Monash University, 19 Innovation Walk, Victoria 3800, Melbourne, Australia;6. Sir Run Shaw Hospital, College of Medicine, Zhenjiang University, 3rd East Qingchun Road, Hangzhou 310016, China |
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Abstract: | ObjectivesPolymyxin 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.MethodsAn 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.ResultsOne 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.ConclusionsThis 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. |
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