Safety and pharmacokinetic evaluation of intravenous colistin methanesulfonate sodium in Japanese healthy male subjects

Author： Mizuyachi Kaori   Hara Katsutoshi   Wakamatsu Akira   Nohda Shigeru   Hirama Toshiyasu  

Publisher： Informa Healthcare

ISSN： 1473-4877

Source： Current Medical Research and Opinion, Vol.27, Iss.12, 2011-12, pp. : 2261-2270

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Abstract

Abstract Objectives:The study aimed at evaluating the pharmacokinetics of colistin methanesulfonate sodium (CMS-Na) and describing observed safety findings in Japanese healthy male subjects. Methods:A total of 22 Japanese healthy males were enrolled in this randomized double-blind, placebo controlled study. Dosing regimens of a single dose and twice-daily repeat doses of CMS-Na (2.5 mg/kg as colistin activity, 75,000 IU/kg) were employed. Safety variables included urinary N-acetyl-β-D-glucosaminidase, protein and β2-microblobulin. Concentrations of CMS and colistin were determined by LC-MS/MS. Pharmacokinetic parameters were obtained by noncompartmental analysis.Clinical trial registration number NCT01449838 Result:The urinary N-acetyl-β-D-glucosaminidase for the detection of early renal damage showed transient increases during the repeat dose period. Otherwise, no clinically significant findings related to study medication were observed. After 2.5-day twice-daily dosing, mean t1/2 and CLR of colistin were 4.98 h and 0.0073 L/h/kg, respectively. Repeat dose Cmax and AUC0–12 were increased by 72%% and 63%%, respectively, compared to single dose. The dosing regimen had little effect on renal excretion rate (fe) of both CMS and colistin. The previously reported area under the unbound concentration–time curve to minimum inhibitory concentration (MIC) ratio (fAUC/MIC) target values in mouse lung and thigh infection models compared with the distribution of fAUC/MIC in humans estimated by a Monte Carlo simulation indicated that a bacteriostatic effect was predicted in 84%% and 96%% of patients, respectively, whereas bactericidal effect was predicted in 65%% and 78%% of patients, respectively. As this study was conducted with a relatively small number of healthy subjects, safety and PK profiles in critically ill patient population may be different than was observed in this study. Conclusion:CMS-Na was safely administered to healthy volunteers but resulted in transient increase of urinary N-acetyl-β-D-glucosaminidase (NAG) and protein. Based on this study, the highest recommended dose of CMS-Na had sufficient bacteriostatic effect.

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