Safety and Clinical Pharmacokinetics of Nemonoxacin, a Novel Non-Fluorinated Quinolone, in Healthy Chinese Volunteers Following Single and Multiple Oral Doses

Self Cite

b Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (C max ) values were 4.826 g/ml, 7.152 g/ml, and 11.029 g/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC 0 -72 h ) were 17.05 g · h/ml, 39.30 g · h/ml, and 61.98 g · h/ml. The mean elimination half-life (t 1/2 ) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. In vitro studies have demonstrated that nemonoxacin exhibits strong broad-spectrum antibacterial activity against Grampositive and Gram-negative bacteria, anaerobes, and atypical pathogens, particularly Staphylococcus spp. and Streptococcus spp. Nemonoxacin shows high antimicrobial activity against multidrug-resistant S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) (1-4). In addition, the drug has been proven to significantly reduce viable bacterial counts in the blood and lungs of mice infected with Streptococcus pneumoniae and to protect animals from lethal infection (5, 6).Completed phase I to III clinical trials of nemonoxacin in China have demonstrated that the drug is rapidly absorbed in healthy subjects after oral administration (at 250-, 500-, and 750-mg doses) and has a long half-life of approximately 11 h. Approximately 70% of the administered drug is excreted by the kidneys. Oral administration of 500 mg or 750 mg nemonoxacin once daily for 10 days is well tolerated in healthy subjects (7). The phase II and III clinical studies also demonstrated that the clinical and microbiological efficacies of oral nemonoxacin (500 mg daily for 7 to 10 days) were comparable to those of oral levofloxacin (500 mg daily) for the treatment of mild to moderate community-acquired pneumonia (CAP). Based on these findings, TaiGen Biotechnology Co., Ltd., developed an intravenous (i.v.) formulation of nemonoxacin for the...

Section: Discussionmentioning

confidence: 67%

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confidence: 99%

Safety, Tolerability, and Pharmacokinetics of Intravenous Nemonoxacin in Healthy Chinese Volunteers

Cao

Zhang

et al. 2014

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“…The profile of intravenous nemonoxacin had characteristics similar to those of the nemonoxacin capsule in healthy volunteers (13). For example, the C max of i.v.…”

Section: Discussionmentioning

confidence: 75%

“…The half-life (t 1/2 ) of nemonoxacin in the capsule formulation was about 11 h, and about 70% of the administered dose was excreted by the kidneys in an unchanged form. The two oral regimens, 500 mg or 750 mg once daily for 10 consecutive days under fasting conditions, were also well tolerated in Chinese subjects (13).…”

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confidence: 99%

Pharmacokinetics and Pharmacodynamics of Multiple-Dose Intravenous Nemonoxacin in Healthy Chinese Volunteers

Zhang

Guo

et al. 2015

Self Cite

cThis study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n ‫؍‬ 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n ‫؍‬ 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ؎ SD) at steady state (C max_ss ) were 9.60 ؎ 1.84 and 11.04 ؎ 2.18 g/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC 0 -24_ss ) were 44.03 ؎ 8.62 and 65.82 ؎ 10.78 g · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin C max_ss values were 7.13 ؎ 1.47, 8.17 ؎ 1.76, and 9.96 ؎ 2.23 g/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC 0 -24_ss values were 40.46 ؎ 9.52, 54.17 ؎ 12.10, and 71.34 ؎ 17.79 g · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was <1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.)

“…Oral nemonoxacin, 750 mg and 500 mg given once daily for 7 days, showed high biological success rates for common bacterial pathogens and high clinical success rates for atypical pathogens of community-acquired pneumonia. Nemonoxacin was well tolerated, and no serious drug-related adverse events were observed (12,13).…”

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confidence: 93%

In Vitro Activity of Nemonoxacin, a Novel Nonfluorinated Quinolone Antibiotic, against Chlamydia trachomatis and Chlamydia pneumoniae

Chotikanatis

Kohlhoff

Hammerschlag

2014

The in vitro activities of nemonoxacin, levofloxacin, azithromycin, and doxycycline were tested against 10 isolates each of Chlamydia trachomatis and Chlamydia pneumoniae. The MICs at which 90% of the isolates of both C. trachomatis and C. pneumoniae were inhibited (MIC 90 s) were 0.06 g/ml (range, 0.03 to 0.13 g/ml). The minimal bactericidal concentrations at which 90% of the isolates were killed by nemonoxacin (MBC 90 s) were 0.06 g/ml for C. trachomatis (range, 0.03 to 0.125 g/ml) and 0.25 for C. pneumoniae (range, 0.015 to 0.5 g/ml).