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-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 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-β-D-glucosaminidase (NAG) and protein. Based on this study, the highest recommended dose of CMS-Na had sufficient bacteriostatic effect.

Key words::

• Colistin methanesulfonate
• Healthy volunteer
• Intravenous
• Pharmacokinetics
• Safety

Transparency

Declaration of funding

This study was funded by GlaxoSmithKline K.K.

Declaration of financial/other relationships

All authors are employees of GlaxoSmithKline, K.K.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

The authors wish to acknowledge that Jennifer R. Yuan (Principal investigator) and Michelle Fryirs (Clinical project manager) of GlaxoSmithKline Medicines Research Unit Australia are highly appreciated for conducting the clinical study. The study preparation by Hidekatsu Motoyama (Project leader), Hiroshi Itoh (Statistician), Yasutaka Moriguchi (Statistical programming and reporting scientist), Hiroshi Yamaguchi (Data manager), Yuji Yamamoto (Programmer), Shinji Yokoyama, Hiroyuki Yoshizaki, Satoru Kimura (pre-clinical scientists), Jean-Philippe Quere (Pharmaceutical development scientist), Sayuri Heshiki (Clinical safety and pharmacovigilance representative), Tasuku Watanabe (Regulatory affairs representative), and Hirokazu Yamashita (Project manager) of GlaxoSmithKline K.K. Japan is noted with gratitude. Quantification of colistin and CMS by Atsuko Tomaru and Masao Shimizu (Bioanalytic scientist) of Shin Nippon Biomedical Laboratories Ltd Japan is greatly acknowledged. This study was funded by GlaxoSmithKline K.K.

The content reported herein is solely the responsibility of the authors.