• Kaori Mizuyachi, Katsutoshi Hara, Akira Wakamatsu, Shigeru Nohda, and Toshiyasu Hirama.
• Clinical Pharmacology Department, Japan. kaori.mizuyachi@gsk.com
• Curr Med Res Opin. 2011 Dec 1; 27 (12): 226122702261-70.

ObjectivesThe study aimed at evaluating the pharmacokinetics of colistin methanesulfonate sodium (CMS-Na) and describing observed safety findings in Japanese healthy male subjects.MethodsA 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 β(2)-microblobulin. Concentrations of CMS and colistin were determined by LC-MS/MS. Pharmacokinetic parameters were obtained by noncompartmental analysis.Clinical Trial Registration NumberNCT01449838.ResultThe 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 t(1/2) and CL(R) of colistin were 4.98 h and 0.0073 L/h/kg, respectively. Repeat dose C(max) and AUC(0-12) 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.ConclusionCMS-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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