AAC Accepts, published online ahead of print on 2 November 2009

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00682-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Nemonoxacin (TG-873870), a Novel Potent Broad-Spectrum Non-Fluorinated Quinolone, in Healthy Volunteers

Luke Lin, Li-Wen Chang, Cheng-Yuan Tsai, Ching-Hung Hsu, David T. Chung^*, William S. Aronstein, Funmi Ajayi, Barbara Kuzmak, and Robert A. Lyon

TaiGen Biotechnology Co. Ltd., Taipei, Taiwan; TI Clinical Trial & Consulting Services Inc., Blue Ash, Ohio 45242; and Procter and Gamble Healthcare, Mason, OH 45040

^* To whom correspondence should be addressed. Email: davidchung{at}taigenbiotech.com.

Nemonoxacin (TG-873870) is a novel non-fluorinated quinolone with potent broad-spectrum activity against Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, penicillin- and quinolone-resistant Streptococcus pneumoniae, and vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. The safety, tolerability, and pharmacokinetics of nemonoxacin were investigated in this double-blind, ascending single-dose study, involving 56 healthy subjects (48 males, 8 females) who were randomly assigned to 1/7 dose cohorts. In each successive cohort, two subjects received a placebo and six received single oral doses of 25, 50, 125, 250, 500, 1000, or 1500 mg nemonoxacin. Nemonoxacin was well tolerated up to the maximum dose of 1500 mg. No severe or serious adverse events were observed. The most frequent adverse events were contact dermatitis, pruritus, and erythema. No clinically significant abnormalities were noted in the ECGs, vital signs, or laboratory tests. The plasma concentrations increased over the dose range, and at 500 mg, the free AUC/MIC₉₀ ratios and free C_max/MIC₉₀ ratios against drug-sensitive/drug-resistant S. pneumoniae and S. aureus were greater than 227 and 24, respectively. The peak time and elimination half-life of nemonoxacin were 12 h and 916 h, respectively. The oral clearance was approximately 0.22 L/h/kg. The plasma protein binding was approximately 16%. The results of this study support further evaluation of the multiple-dose safety, tolerability, and pharmacokinetics of nemonoxacin.