Clinical Drug Investigation

, Volume 32, Issue 7, pp 475–486 | Cite as

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

  • Beining Guo
  • Xiaojie Wu
  • Yingyuan Zhang
  • Yaoguo Shi
  • Jicheng Yu
  • Guoying Cao
  • Jing Zhang
Original Research Article

Abstract

Background: Nemonoxacin, 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.

Objective: The 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.

Methods: The 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.

Results: No 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 (Cmax) attained 1–2 hours after administration. The Cmax 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 Cmax from 1.14 to 3.64 hours and reducing Cmax by 34% and AUC by 18%, while a sex effect was not found. Cmax 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.

Conclusion: Nemonoxacin 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.

Notes

Acknowledgements

We thank TaiGen Biotechnology Company Ltd, Taipei, Taiwan for their support of the study and for reviewing the manuscript. The work was also supported by a grant from the Ministry of Science and Technology of China (2008ZX09312–010).

Beining Guo and Xiaojie Wu contributed equally to this work.

References

  1. 1.
    Peterson LR. Quinolone molecular structure-activity relationships: what we have learned about improving antimicrobial activity. Clin Infect Dis 2001; 33 Suppl. 3: 180–6CrossRefGoogle Scholar
  2. 2.
    Andersson MI, MacGowan AP. Development of the quinolones. J Antimicrob Chemother 2003; 51 Suppl. 1: 1–11PubMedCrossRefGoogle Scholar
  3. 3.
    Adam HJ, Laing NM, King CR, et al. In vitro activity of nemonoxacin, a novel nonfluorinated quinolone, against 2,440 clinical isolates. Antimicrob Agents Chemother 2009; 53: 4915–20PubMedCrossRefGoogle Scholar
  4. 4.
    Chen YH, Liu CY, Lu JJ, et al. In vitro activity of nemonoxacin (TG-873870), a novel non-fluorinated quinolone, against clinical isolates of Staphylococcus aureus, enterococci and Streptococcus pneumoniae with various resistance phenotypes in Taiwan. J Antimicrob Chemother 2009; 64: 1226–9PubMedCrossRefGoogle Scholar
  5. 5.
    Lai CC, Tan CK, Lin SH, et al. Comparative in vitro activities of nemonoxacin, doripenem, tigecycline and 16 other antimicrobials against Nocardia brasiliensis, Nocardia asteroides and unusual Nocardia species. J Antimicrob Chemother 2009; 64: 73–8PubMedCrossRefGoogle Scholar
  6. 6.
    Lauderdale TL, Shiau YR, Lai JF, et al. Comparative in vitro activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, and other quinolones against clinical isolates. Antimicrob Agents Chemother 2010; 54: 1338–42PubMedCrossRefGoogle Scholar
  7. 7.
    Li CR, Li Y, Li GQ, et al. In vivo antibacterial activity of nemonoxacin, a novel non-fluorinated quinolone. J Antimicrob Chemother 2010; 65: 2411–5PubMedCrossRefGoogle Scholar
  8. 8.
    Lin L, Chang LW, Tsai CY, et al. Dose escalation study of the safety, tolerability, and pharmacokinetics of nemonoxacin (TG-873870), a novel potent broad-spectrum nonfluorinated quinolone, in healthy volunteers. Antimicrob Agents Chemother 2010; 54: 405–10PubMedCrossRefGoogle Scholar
  9. 9.
    Chung DT, Tsai CY, Chen SJ, et al. Multiple-dose safety, tolerability, and pharmacokinetics of oral nemonoxacin (TG-873870) in healthy volunteers. Antimicrob Agents Chemother 2010; 54: 411–7PubMedCrossRefGoogle Scholar
  10. 10.
    Guo B, Zhang J, Yu J, et al. 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. Biomed Chromatogr 2012 Jan 24: doi: 10.1002/bmc.2699Google Scholar
  11. 11.
    Chow CP, Tsai CY, Yeh CF, et al. In vitro metabolism and interaction of nemonoxacin (TG-873870) on human hepatic CYP3A4. In: Abstracts of the Four-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago (IL) 2007 [Abstract A-27]. American Society for Microbiology, Washington, DC, USAGoogle Scholar
  12. 12.
    Owens Jr RC, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis 2005; 41 Suppl. 2: 144–57CrossRefGoogle Scholar
  13. 13.
    Stass H, Dalhoff AD, Kubitza D, et al. Pharmacokinetics, safety, and tolerability of ascending single-doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Antimicrob Agents Chemother 1998; 42: 2060–5PubMedGoogle Scholar
  14. 14.
    Allen A, Bygate E, Oliver S, et al. Pharmacokinetics and tolerability of gemifloxacin (SB-265805) after administration of single oral doses to healthy volunteers. Antimicrob Agents Chemother 2000; 44: 1604–8PubMedCrossRefGoogle Scholar
  15. 15.
    Chien SC, Wong FA, Fowler CL, et al. Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers. Antimicrob Agents Chemother 1998; 42: 885–8PubMedGoogle Scholar
  16. 16.
    Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26: 1–12PubMedCrossRefGoogle Scholar
  17. 17.
    Drusano GL. Pharmacokinetics and pharmacodynamics of antimicrobials. Clin Infect Dis 2007; 45 Suppl. 1: 89–95CrossRefGoogle Scholar
  18. 18.
    Andes D, Craig WA. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Chemother 2002; 19: 261–8CrossRefGoogle Scholar
  19. 19.
    Ambrose PG, Grasela DM, Grasela TH, et al. Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections. Antimicrob Agents Chemother 2001; 45: 2793–7PubMedCrossRefGoogle Scholar
  20. 20.
    Drusano GL, Preston SL, Fowler C, et al. Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia. J Infect Dis 2004; 189: 1590–7PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • Beining Guo
    • 1
    • 2
  • Xiaojie Wu
    • 1
    • 2
  • Yingyuan Zhang
    • 1
    • 2
  • Yaoguo Shi
    • 1
    • 2
  • Jicheng Yu
    • 1
    • 2
  • Guoying Cao
    • 1
    • 2
  • Jing Zhang
    • 1
    • 2
  1. 1.Institute of Antibiotics, Huashan HospitalFudan UniversityShanghai, 200040China
  2. 2.Key Laboratory of Clinical Pharmacology of AntibioticsMinistry of HealthShanghaiChina

Personalised recommendations