Pharmacokinetics of colistin methanesulfonate (CMS) in healthy Chinese subjects after single and multiple intravenous doses

Miao Zhao, Xiao-Jie Wu, Ya-Xin Fan, Ying-yuan Zhang, Bei-Ning Guo, Ji-cheng Yu, Guo-ying Cao, Yuan-cheng Chen, Ju-fang Wu, Yao-guo Shi, Jian Li, Jing Zhang

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Abstract

The high prevalence of extensively drug-resistant Gram-negative pathogens has forced clinicians to use colistin as a last-line therapy. Knowledge on the pharmacokinetics of colistin methanesulfonate (CMS), an inactive prodrug, and colistin has increased substantially; however, the pharmacokinetics in the Chinese population is still unknown due to lack of a CMS product in China. This study aimed to evaluate the pharmacokinetics of a new CMS product developed in China in order to optimise dosing regimens. A total of 24 healthy subjects (12 female, 12 male) were enrolled in single- and multiple-dose pharmacokinetic (PK) studies. Concentrations of CMS and formed colistin in plasma and urine were measured, and PK analysis was conducted using a non-compartmental approach. Following a single CMS dose [2.36 mg colistin base activity (CBA) per kg, 1 h infusion], peak concentrations (Cmax) of CMS and formed colistin were 18.0 mg/L and 0.661 mg/L, respectively. The estimated half-life (t1/2) of CMS and colistin were 1.38 h and 4.49 h, respectively. Approximately 62.5% of the CMS dose was excreted via urine within 24 h after dosing, whilst only 1.28% was present in the form of colistin. Following multiple CMS doses, colistin reached steady-state within 24 h; there was no accumulation of CMS, but colistin accumulated slightly (RAUC = 1.33). This study provides the first PK data in the Chinese population and is essential for designing CMS dosing regimens for use in Chinese hospitals. The urinary PK data strongly support the use of intravenous CMS for serious urinary tract infections.

Original languageEnglish
Pages (from-to)714-720
Number of pages7
JournalInternational Journal of Antimicrobial Agents
Volume51
Issue number5
DOIs
Publication statusPublished - 1 May 2018
EventInterscience Conference on Antimicrobial Agents and Chemotherapy - San Diego, United States of America
Duration: 17 Sep 201521 Sep 2015
Conference number: 55

Keywords

  • Colistin methanesulfonate
  • Pharmacokinetics
  • Urinary recovery

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