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

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-ß-D-glucosaminidase, protein and ß(2)-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-ß-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. CONCLUSION: CMS-Na was safely administered to healthy volunteers but resulted in transient increase of urinary N-acetyl-ß-D-glucosaminidase (NAG) and protein. Based on this study, the highest recommended dose of CMS-Na had sufficient bacteriostatic effect.