A liquid chromatography–tandem mass spectrometry assay for the determination of nemonoxacin (TG‐873870), a novel nonfluorinated quinolone, in human plasma and urine and its application to a single‐dose pharmacokinetic study in healthy Chinese volunteers

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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: Discussioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

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

Cao

Zhang

et al. 2014

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“…The determination of nemonoxacin levels was performed using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method according to our previous work (5). In detail, the LC-MS/MS system included a Waters 2690 module (Waters Co. Ltd., Milford, MA) in tandem with the TSQ Quantum Discovery Max mass spectrometer (Thermo Finnigan Co. Ltd., San Jose, CA).…”

Section: Strainsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Nemonoxacin against Streptococcus pneumoniae in an In Vitro Infection Model

Wang

Chen

Cao

et al. 2013

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The aim of this paper was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of nemonoxacin, a novel nonfluorinated quinolone, against Streptococcus pneumoniae in vitro. A modified infection model was used to simulate the pharmacokinetics of nemonoxacin following scaling of single oral doses and multiple oral dosing. Four S. pneumoniae strains with different penicillin sensitivities were selected, and the drug efficacy was quantified by the change in log colony counts within 24 h. A sigmoid maximum-effect (E max ) model was used to analyze the relationship between PK/PD parameters and drug effect. Analysis indicated that the killing pattern of nemonoxacin shows a dualism which is mainly concentration dependent when the MIC is low and that the better PK/PD index should be the area under the concentration-time curve for the free, unbound fraction of the drug divided by the MIC (fAUC 0 -24 /MIC), which means that giving the total daily amount of drug as one dose is appropriate under those conditions. When the MIC is high, the time (T) dependency is important and the valid PK/PD index should be the cumulative percentage of a 24-h period in which the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (f%T>MIC), which means that to split the maximum daily dose into several separate doses will benefit the eradication of the bacteria. To obtain a 3-log 10 -unit decrease, the target values of fAUC 0 -24 /MIC and f%T>MIC are 47.05 and 53.4%, respectively. N emonoxacin, a novel nonfluorinated quinolone, exerts broad antibacterial activity by interrupting DNA synthesis in prokaryotic organisms (1). The antimicrobial spectrum includes Gram-positive and Gram-negative bacteria as well as atypical pathogens such as penicillin-resistant Streptococcus pneumoniae and methicillin-and vancomycin-resistant Staphylococcus aureus (2, 3). The antibacterial activity of nemonoxacin is stronger than that of levofloxacin and moxifloxacin against most Gram-positive cocci (4).Completed phase I clinical trials in China have demonstrated that nemonoxacin is well tolerated within the dose range of 125 to 1,000 mg and shows linear pharmacokinetics. The absorption peak appeared at 1 to 2 h, and the elimination half-life was 10 to 12 h (5). In a phase II clinical trial, the effect of nemonoxacin (500 or 750 mg daily for 7 to 10 days) was similar to that of 500 mg levofloxacin for treating community-acquired pneumonia (CAP) in adults (6). A phase III clinical trial has just completed. However, few studies have investigated the killing pattern and pharmacokinetic/pharmacodynamic (PK/PD) characteristics of this drug, which are needed for the dose regimen design.Compared to animal models, the PK process of the drug in humans could be well simulated in the in vitro models without considering species differences between human and animals (7, 8). Meanwhile, in vitro models allow determination of time-kill behavior and identification and optimization of PK/PD indices and breakpoints (9). In the present work, we...

“…The concentrations of nemonoxacin in human blood and urine samples were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods as reported by Guo et al (15). The LC-MS/MS system included a Waters Alliance 2690 high-pressure liquid chromatograph and Finnigan TSQ Quantum mass spectrometer (Waters Co., Milford, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

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

Zhang

Guo

et al. 2015

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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.)