Dose findings of antofloxacin hydrochloride for treating bacterial infections in an early clinical trial using PK-PD parameters in healthy volunteers

Li, Yunfei; Wang, Kun; Yin, Fang; He, Yingchun; Huang, Jihan; Zheng, Qingshan

doi:10.1038/aps.2012.68

Cited by 9 publications

(8 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This microbiological response in the animal model was analogous to, or in excess of, that of the currently available "respiratory" fluoroquinolones levofloxacin and moxifloxacin, which required an AUC 0 -24 /MIC ratio of Ͼ100 to produce a significant bactericidal effect (12). Once more, an early clinical trial showed that antofloxacin had clinical and bacteriological outcomes for K. pneumoniae (30 strains) and E. coli (33 strains) similar to those of levofloxacin (13). In general, fluoroquinolones have good penetration into ELF, and our study confirms this observation (14,15).…”

Section: Discussionmentioning

confidence: 82%

In Vivo Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model

Zhou

Tao

Huo

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven Klebsiella pneumoniae isolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally with K. pneumoniae and treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. The E max Hill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log 10 or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentrationtime curve over 24 h (AUC 0 -24 )/MIC ratio was the PD index most closely linked to efficacy (R 2 ϭ 0.96). The mean free-drug AUC 0 -24 /MIC ratios required to achieve net bacterial stasis, a 1-log 10 kill, and a 2-log 10 kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involving K. pneumoniae. KEYWORDS antofloxacin, PK/PD, murine lung infection, Klebsiella pneumoniaeA cute exacerbations of chronic bronchitis (AECB) represent an important health burden to patients, including increased morbidity, mortality, and health care costs worldwide (1, 2). Although viral infections have an important role in both development and progression of AECB, the pathophysiological mechanisms are not completely understood and seem to be a complex of many interrelated factors (3). Apart from exacerbations caused by viral infections and environmental irritants, approximately 40 to 50% of exacerbations are attributed to bacteria that include Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae, and Staphylococcus spp. (4). It is a common practice to prescribe antibiotics for AECB patients with severe illness (5, 6). However, treatment of these bacterial infections is frequently challenging due to drug resistance and limited therapeutic options.

show abstract

Section: Discussionmentioning

confidence: 82%

In Vivo Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model

Zhou

Tao

Huo

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Previous studies showed that the protein binding rate of chinfloxacin was 17.5%, the MIC 90 range was 0.03 to 1 mg/liter for most clinical isolates, and the AUC ss was around 51.53 mg·h·liter Ϫ1 after multiple oral administrations of 400 mg. The AUC ss value from the 400-mg multiple-dose PK study could make the fAUC ss /MIC of chinfloxacin higher than the PK/PD breakpoints of fluoroquinolones related to clinical efficacy and thereby meet the therapeutic target value of fluoroquinolones for clinical use (19)(20)(21). This suggests that 400 mg of chinfloxacin is an appropriate dose for future clinical study.…”

Section: Discussionmentioning

confidence: 99%

A Randomized Study of the Single-Dose Safety, Pharmacokinetics, and Food Effect of Chinfloxacin and Its Effect on Thorough QT/QTc Interval in Healthy Chinese Volunteers

Zhao

Wei

et al. 2018

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Chinfloxacin hydrochloride is a novel tricyclic fluorinated quinolone in development for treatment of conventional and biothreat infections. This first-in-human randomized study in Chinese healthy subjects was divided into 5 parts. Part A was a single-ascending-dose study to assess safety and tolerability of chinfloxacin. The single-dose pharmacokinetic study, a food effect study, and a multiple-dose pharmacokinetics study were conducted in parts B, C, and D, respectively. Part E was a randomized, placebo-controlled and positive-control single-dose, crossover study to evaluate the effect of chinfloxacin on thorough electrocardiographic QT/corrected QT (QTc) interval. The results suggest that single and multiple oral administrations of chinfloxacin were well tolerated. The observed adverse events (AEs) were dizziness, nausea, weakness, photosensitive dermatitis, and increased frequency of defecation. All AEs were mild and were resolved spontaneously without any treatment. The time to peak plasma concentration ( and , respectively) was about 2 h, and the half-life was 14 to 16 h. Food slightly affected the drug's rate and extent of absorption, increasing the from 1.60 to 2.59 h and reducing the by 13.6% and area under the concentration-time curve by 8.95%. Chinfloxacin at 400 mg had no effect on prolongation of QT/QTc intervals. Although 600 mg chinfloxacin had a mild effect on the prolongation of the QT/QTc interval, the effect was less pronounced than that of the positive control, 400 mg moxifloxacin. The pharmacokinetics and safety profiles of chinfloxacin in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (This study has been registered at www.ChiCTR.org.cn under identifiers ChiCTR-TRC-10001619 for parts A to D and ChiCTR1800015906 for part E.).

show abstract

“…In recent years, high‐performance liquid chromatography (HPLC) has been the most commonly used method in analyzing antofloxacin and its derivatives (Xiao et al, ; Li et al, ). In most of the previous work, the parent drug was the only parameter that has been analyzed.…”

Section: Introductionmentioning

confidence: 99%

“…In most of the previous work, the parent drug was the only parameter that has been analyzed. Nevertheless, the cumulative urinary elimination percentage of antofloxacin after the last dose within 96 h was no more than 56% (Xiao et al, ; Li et al, ). It was a time‐consuming method with undesired results; new method needs to be established to shorten the analysis time and raise the sensitivity and accuracy.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous quantification of antofloxacin and its major metabolite in human urine by HPLC–MS/MS, and its application to a pharmacokinetic study

Zhang

Xie

et al. 2017

Biomedical Chromatography

View full text Add to dashboard Cite

This study presents a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the simultaneous determination of antofloxacinin and its main metabolite - N-demethylated metabolite (N-DM) - in human urine. Ornidazole was used as the internal standard. This was a clinical urine recovery study, in which 10 healthy Chinese volunteers were intravenously administered a single 200 mg dose of antofloxacin hydrochloride. Compounds were extracted by albumen precipitation, after which samples were isocratically eluted using a Poroshell 120 SB-C column, and were analysed using HPLC-MS/MS under electronic spray ionization positive ion mode. The method was successfully applied in a urine pharmacokinetic study of antofloxacinin, with a detection range of 0.02/0.01 to 200/100 μg/mL (for antofioxacin/N-DM).The average percentages of antofioxacin/N-DM measured in urinary excretion frp, 10 volunteers were 54.9 ± 5.7/8.2 ± 2.5% in 120 h duration.

show abstract

Dose findings of antofloxacin hydrochloride for treating bacterial infections in an early clinical trial using PK-PD parameters in healthy volunteers

Cited by 9 publications

References 14 publications

In Vivo Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model

In Vivo Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model

A Randomized Study of the Single-Dose Safety, Pharmacokinetics, and Food Effect of Chinfloxacin and Its Effect on Thorough QT/QTc Interval in Healthy Chinese Volunteers

Simultaneous quantification of antofloxacin and its major metabolite in human urine by HPLC–MS/MS, and its application to a pharmacokinetic study

Contact Info

Product

Resources

About