• Beining Guo, Xiaojie Wu, Yingyuan Zhang, Yaoguo Shi, Jicheng Yu, Guoying Cao, and Jing Zhang.
• Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
• Clin Drug Investig. 2012 Jul 1;32(7):475-86.

BackgroundNemonoxacin, a novel C-8-methoxy non-fluorinated quinolone, is currently being developed in oral and intravenous formulations. It exhibits potent antibacterial activities against Gram-positive, Gram-negative and atypical pathogens, especially methicillin-resistant Staphylococcus aureus. The first-in-human study of a nemonoxacin capsule was conducted in a Western population. This current study was the first investigation on the clinical pharmacokinetics (PK) of nemonoxacin in a Chinese population, and was designed to determine PK data in a Chinese population and investigate the dose regimen for future clinical use.ObjectiveThe objective of this study was to evaluate the PK profile of nemonoxacin as well as its safety and tolerability in healthy Chinese volunteers following single and multiple oral doses.MethodsThe first part of the study was a double-blind, placebo-controlled, sequential ascending single-dose safety and tolerability study. In each cohort, two subjects received a placebo and six received single oral doses of nemonoxacin 125, 250, 500, 750 or 1000 mg. In the second part, the single-dose PK study, three dose levels (250, 500 and 750 mg) of nemonoxacin were administered orally to 12 healthy Chinese volunteers (male : female = 1 : 1) under fasting conditions in a crossover manner. The same volunteers received orally an additional dose of 500 mg under fed conditions after a 7-day washout. In the third part, the multiple-dose PK study, 24 subjects received 500 or 750 mg of nemonoxacin orally once daily for 10 consecutive days. Within each cohort, 12 subjects (male : female = 1 : 1) received the same dose level of nemonoxacin under fasting conditions. The PK profiles, safety and tolerability, and food and sex effects were evaluated.ResultsNo severe or serious adverse events (AEs) occurred in this study, and no clinically significant abnormalities were noted in the vital signs or on physical examination. Notable AEs, mainly nausea and rash with or without pruritus, were mild and resolved spontaneously. Most laboratory AEs were mild and transient and the subjects recovered without treatment. Nemonoxacin was found to be rapidly absorbed, with peak plasma concentrations (C(max)) attained 1-2 hours after administration. The C(max) and area under the concentration-time curve from time zero to infinity (AUC(∞)) were dose-proportional after single oral doses. The elimination half-life was 10-12 hours. Nemonoxacin was excreted primarily in urine, with a recovery of intact nemonoxacin of 60-70% of the dose over 72 hours. Food had a significant effect on the rate and extent of absorption (p < 0.001), increasing the time to reach C(max) from 1.14 to 3.64 hours and reducing C(max) by 34% and AUC(∞) by 18%, while a sex effect was not found. C(max) and AUC(∞) were similar between the single-dose and multiple-dose PK studies. The multiple-dose PK data suggested no drug accumulation in healthy subjects.ConclusionNemonoxacin exhibited a linear PK profile in the 250-750 mg dose range with moderate food effects. There was no accumulation following consecutive administration for 10 days. The PK and safety profiles of nemonoxacin in Chinese subjects support evaluation of once-daily dosing in the future development of this agent.

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