Efficacy and Safety of Antofloxacin-Based Triple Therapy for Helicobacter pylori Eradication Failure in China.

AIMS: Quinolone-containing triple therapy has been considered as the second-line therapy for eradication of Helicobacter pylori (H. pylori). At present, there are no data to show the efficacy and safety of antofloxacin-based rescue therapy for the eradication of H. pylori, and this pilot clinical trial was designed. METHODS: A total of 196 patients who failed H. pylori eradication using the clarithromycin-based or metronidazole-based triple or bismuth quadruple therapy were randomly allocated to one of the following rescue eradication therapy groups: AEA group (antofloxacin 200 mg once daily, esomeprazole 20 mg + amoxicillin 1000 mg twice daily) for 14 days, or LEA group (levofloxacin 500 mg once daily, esomeprazole 20 mg + amoxicillin 1000 mg twice daily) for 14 days. The minimal inhibitory concentrations were tested by the E-test method. The gyrA mutation was analyzed by sequencing. Follow-up 13/14C-urea breath test was examined at 1 month after discontinuation. RESULTS: A total of 178 eligible patients were included in this study. The eradication rate was significantly higher in AEA group than in LEA group according to both ITT (87.6% vs. 68.5%; P = 0.002) and PP analyses (90.7% vs. 70.1%; P = 0.001). ITT analyses indicated that the eradication rate was significantly higher in AEA group than in LEA group with Asn87 mutation (78.9% vs. 31.3%; P = 0.005) and levofloxacin-resistant strains (76.9% vs. 44.2%; P = 0.003). Two groups exhibited similar adverse event rates (AEA 14.6% vs. LEA 20.2%, P = 0.323). CONCLUSIONS: The findings showed that antofloxacin may be a promising candidate in rescue therapy for H. pylori eradication failure in China.

In Vivo Pharmacodynamic Target Assessment of Antofloxacin against Streptococcus pneumoniae and Staphylococcus aureus in a Neutropenic Murine Pneumonia Model.

We determined in vivo efficacy and target PK/PD exposures of antofloxacin against Streptococcus pneumoniae and Staphylococcus aureus in the murine pneumonia model. The mean plasma free drug area under the concentration-time curve/MIC (fAUC/MIC) targets associated with stasis and 1-log10 and 2-log10 kill effects were 8.93, 19.2, and 48.1, respectively, for S. pneumoniae, whereas they were 30.5, 55.4, and 115.8, respectively, for S. aureus The fAUC/MIC targets in murine lung epithelial lining fluids (ELF) for the same endpoints were nearly 2-fold higher than those in plasma.

In Vivo Bioluminescent Monitoring of Therapeutic Efficacy and Pharmacodynamic Target Assessment of Antofloxacin against Escherichia coli in a Neutropenic Murine Thigh Infection Model.

Antimicrobial resistance among uropathogens has increased the rates of infection-related morbidity and mortality. Antofloxacin is a novel fluoroquinolone with broad-spectrum antibacterial activity against urinary Gram-negative bacilli, such as Escherichia coli This study monitored the in vivo efficacy of antofloxacin using bioluminescent imaging and determined pharmacokinetic (PK)/pharmacodynamic (PD) targets against E. coli isolates in a neutropenic murine thigh infection model. The PK properties were determined after subcutaneous administration of antofloxacin at 2.5, 10, 40, and 160 mg/kg of body weight. Following thigh infection, the mice were treated with 2-fold-increasing doses of antofloxacin from 2.5 to 80 mg/kg administered every 12 h. Efficacy was assessed by quantitative determination of the bacterial burdens in thigh homogenates and was compared with the bioluminescent density. Antofloxacin demonstrated both static and killing endpoints in relation to the initial burden against all study strains. The PK/PD index area under the concentration-time curve (AUC)/MIC correlated well with efficacy (R2 = 0.92), and the dose-response relationship was relatively steep, as observed with escalating doses of antofloxacin. The mean free drug AUC/MIC targets necessary to produce net bacterial stasis and 1-log10 and 2-log10 kill for each isolate were 38.7, 66.1, and 147.0 h, respectively. In vivo bioluminescent imaging showed a rapid decrease in the bioluminescent density at free drug AUC/MIC exposures that exceeded the stasis targets. The integration of these PD targets combined with the results of PK studies with humans will be useful in setting optimal dosing regimens for the treatment of urinary tract infections due to E. coli.

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

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 Emax 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-log10 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 concentration-time curve over 24 h (AUC0-24)/MIC ratio was the PD index most closely linked to efficacy (R2 = 0.96). The mean free-drug AUC0-24/MIC ratios required to achieve net bacterial stasis, a 1-log10 kill, and a 2-log10 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.

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

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-C18 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.

Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin.

Antofloxacin (AFX) is a novel fluoroquinolone that has been approved in China for the treatment of infections caused by a variety of bacterial species. We investigated whether it could be repurposed for the treatment of tuberculosis by studying its in vitro activity. We determined the wild-type and non-wild-type MIC ranges for AFX as well as ofloxacin (OFX), levofloxacin (LFX), and moxifloxacin (MFX), using the microplate alamarBlue assay, of 126 clinical Mycobacterium tuberculosis strains from Beijing, China, of which 48 were OFX resistant on the basis of drug susceptibility testing on Löwenstein-Jensen medium. The MIC distributions were correlated with mutations in the quinolone resistance-determining regions of gyrA (Rv0006) and gyrB (Rv0005). Pharmacokinetic/pharmacodynamic (PK/PD) data for AFX were retrieved from the literature. AFX showed lower MIC levels than OFX but higher MIC levels than LFX and MFX on the basis of the tentative epidemiological cutoff values (ECOFFs) determined in this study. All strains with non-wild-type MICs for AFX harbored known resistance mutations that also resulted in non-wild-type MICs for LFX and MFX. Moreover, our data suggested that the current critical concentration of OFX for Löwenstein-Jensen medium that was recently revised by the World Health Organization might be too high, resulting in the misclassification of phenotypically non-wild-type strains with known resistance mutations as wild type. On the basis of our exploratory PK/PD calculations, the current dose of AFX is unlikely to be optimal for the treatment of tuberculosis, but higher doses could be effective.

[Treatment of trophic ulsers of different etiology].

The research included 40 patients with chronic trophic ulcers of lower extremities of different etiology (arterial insufficiency - 14 patients, venous insufficiency - 20 patients, diabetic foot syndrome - 6 people). According to the data of prime bacteriological inoculation, the main pathogens were: gram-positive coccus (Staphylococcus spp., Staphylococcus aureus - 75%, Staphylococcus epidermidis - 7,5%) and yeast-like fungi (Candida albicans - 7,5%). Microbial semination in plentiful quantity (more than 106 KOE) was detected at first inoculation in 85% of the patients. The ointment was applied for the patients. After 20 days, the lack of growth and the decrease of contamination level (lower than critical (less than 102 KOE) were noted. A visual analog scale estimated an intensity of pain in patients and it consisted of 39,8% before the treatment, 27,1% - after 10 days, 14,6% - after 20 days. The "Oflomelid" application allowed the reduction of the terms of wound cleansing from nonviable tissues in majority of patients and gained the fast transition from the granulation to epithelization phase. The principle of wound management with the application of ointment "Oflomelid" should be followed in a moist environment. A modern wound dressing must be used after the ointment. This shortened the terms of separate-phase wound repair and decreased the terms of the whole period of trophic ulcers repair in patients with vascular and endocrine pathology.

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

AIM: To find an appropriate dose regimen of the novel antibacterial agent antofloxacin for a phase II clinical trial using a population pharmacokinetic (PPK) study in healthy volunteers and the minimum inhibitory concentration (MIC) as pharmacodynamic (PD) parameters. METHODS: Twenty-four healthy volunteers were enrolled in a double-blind crossover study and received antofloxacin (200 or 400 mg/d, po) for consecutive 5 d with 10 d washout between two separate periods. Blood concentrations were analyzed using HPLC with a UV-Vis detector. The values of area under the curve (AUC) with covariates were obtained from a PPK model, and the MICs came from the previous in vitro studies. The dose regimen was determined for the phase II clinical trial according to the ratio (>20) of AUC/MIC, and the efficacy of the dose was evaluated by the trial. RESULTS: A two-compartment model best described the time-concentration data with first-order absorption. The PPK parameter estimates for CL, V(c), Q, V(p) and K(A) are 8.34 L/h, 142 L, 15.9 L/h, 52.2 L and 4.64 1/h, respectively. The covariates sex for K(A), weight for CL, weight for V(c) and interoccasion variability were included in the final model. The AUC/MIC was calculated based on the PPK model and the MIC of antofloxacin for Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus and Staphylococcus epidermidis were determined in previous researches. The 400 mg loading dose with 200 mg/d maintenance dose was recommended and confirmed by the phase II trial. CONCLUSION: The ratio of AUC from the PPK model vs MIC as the PD parameter can be applied in a dose-finding trial of antofloxacin in treatment of bacterial infections. The PPK model suggests that sex and body weight may be considerations in regards to individual therapy, which should be investigated in larger clinical trials and serve as a potential reference for clinical therapies.

Modulation of pharmacokinetics of theophylline by antofloxacin, a novel 8-amino-fluoroquinolone, in humans.

AIM: To evaluate the pharmacokinetic interactions between theophylline and antofloxacin in vivo and in vitro. METHODS: A randomized, 5-day treatment and 3-way crossover design was documented in 12 healthy subjects. The subjects were orally administered with antofloxacin (400 mg on d 1 and 200 mg on d 2 to 5), theophylline (100 mg twice a day and morning dose 200 mg on d 1 and 5), or theophylline plus antofloxacin. The plasma and urinary pharmacokinetics of antofloxacin and theophylline were characterized after the first and last dose. The effect of antofloxacin on theophylline metabolism was also investigated in pooled human liver microsomes. RESULTS: The 5-day treatment with antofloxacin significantly increased the area of the plasma concentration-time curve and peak plasma concentration of theophylline, accompanied by a decrease in the excretion of theophylline metabolites. On the contrary, theophylline did not affect the pharmacokinetics of antofloxacin. In vitro studies using pooled human hepatic microsomes demonstrated that antofloxacin was a weak reversible and mechanism-based inhibitor of CYP1A2. The clinical interaction between theophylline and antofloxacin was further validated by the in vitro results. CONCLUSION: The results showed that antofloxacin increases the plasma theophylline concentration, partly by acting as a mechanism-based inhibitor of CYP1A2.

Pharmacokinetics of antofloxacin hydrochloride in healthy male subjects after multiple intravenous dose administration.

The purpose of the study was to evaluate pharmacokinetic characteristics of antofloxacin hydrochloride, a new fluoroquinolone antibiotic, during a multiple, intravenous dosing regimen. Twelve healthy, Chinese male volunteer subjects were each given 300 mg of antofloxacin by intravenous infusion once daily for 7 days. Blood and urine samples were taken at designated time points for analysis of antofloxacin concentration by high-performance liquid chromatography (HPLC). Safety and tolerability were assessed by evaluation of subject complaints, vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, haematology and urinalysis and prothrombin time. The serum steady concentration of antofloxacin was obtained in 96 h after the administration of a daily intravenous dose of 300 mg of the drug. In the present study, the following pharmacokinetic parameters after 7 days of treatment with antofloxacin were determined to be: C(max) 3.81 ± 0.66 mg/L, C(min) 0.85 ± 0.19 mg/L, AUC(0-24) 60.51 ± 8.30 mg/L·h, C(av) 2.52 ± 0.35 mg/L, PTF 87.45 ± 3.37%, t(1/2)ß 20.34 ± 1.88 h. The C(max) and AUC(0-24) after 7-day treatment were both higher than after the first dose (by 43% and 110%, respectively). The cumulative urinary elimination of antofloxacin within 96 h after the last dose was about 56%. During the study, there were neither subject complaints nor significant adverse clinical findings. Antofloxacin, administered intravenously as a single, daily 300 mg dose for 7 days, demonstrated favourable pharmacokinetic characteristics and tolerability. The results of this study indicate that antofloxacin hydrochloride is suitable for further clinical study.

[A multi-center, randomized, controlled, double blind and double dummy clinical trial of antofloxacin hydrochloride tablet versus levofloxacin tablet for the treatment of acute bacterial infections].

OBJECTIVE: To evaluate the clinical efficacy and safety of antofloxacin hydrochloride tablet for the treatment of acute bacterial infections. METHODS: A multi-center randomized control, double blind and double dummy clinical trial was conducted; levofloxacin tablet was closed as controlled drug. The duration of treatment was 7-14 days in both groups. RESULTS: A total of 719 patients were enrolled in the study, in which 359 patients treated with antofloxacin and 360 patients treated with levofloxacin were included. Three hundred and thirty and 337 patients completed the study and met with all the criteria for per-protocol analysis, respectively. By the end of chemotherapy, the cured rates in per protocol set (PPS) population were 79.7% and 77.4%, the effective rates were 95.2% and 96.7%, and the bacterial clearance were 96.7% and 97.5% for the treating and control group, respectively. The clinical and bacterial efficacy of antofloxacin and levofloxacin was comparable by the analysis of infectious sites. Three hundred and fifty-seven and 356 patients in antofloxacin and levofloxacin groups were evaluated the safety. The drug adverse events occurred both in 10.1%, and drug adverse reactions occurred in 7.8% and 7.9% patients in the two groups. The most common drug adverse reactions were mild gastroenteric symptoms. No QTc prolongation was detected in all the patients. One patient in each group had mild blood glucose increase at the end of therapy, but the glucose returned to normal level without any intervention. No statistic significant difference between the two groups in clinical efficacy and safety was detected (P > 0.05). CONCLUSIONS: Antofloxacin hydrochloride tablet was effective and safe for the treatment of acute bacterial infections.

Antofloxacin-based bismuth quadruple therapy is safe and effective in Helicobacter pylori eradication: A prospective, open-label, randomized trial.

BACKGROUND AND STUDY AIMS: The present study was designed to evaluate the safety, efficacy, and tolerability of antofloxacin-based bismuth quadruple therapy in Chinese patients with Helicobacter pylori infection. PATIENTS AND METHODS: Total 290 patients with H. pylori infection were randomly and equally divided into two groups as per different bismuth quadruple therapies for 14 d: colloidal bismuth pectin 200 mg thrice a day, lansoprazole 30 mg twice a day, amoxicillin 1 g twice a day, and antofloxacin 200 mg once a day (ACLA group) or levofloxacin 500 mg once a day (LCLA group). Eradication was assessed with 13C-urea breath test 6 wk after treatment completion; the primary endpoint was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. The minimum inhibitory concentration was measured with the PDM epsilometer test to assess the susceptibility of H. pylori strains on gastric biopsy specimens to antofloxacin and levofloxacin. RESULTS: The eradication rates of H. pylori in the ACLA group were 93.8% and 97.8% for the ITT and PP analysis, respectively; these rates were significantly higher than those in the LCLA group, at 86.2% and 92.6%, respectively (p = 0.031 and 0.041, respectively). The total incidence of adverse events during the eradication therapy did not significantly differ between the ACLA and LCLA groups (31.7% vs. 37.9%%, p = 0.267), and the two groups displayed similar severity of adverse events (p = 0.156) and compliance rate (100% by ACLA vs. 97.8% by LCLA, p = 0.080). The eradication rate with the antofloxacin susceptible strains in the ACLA group was significantly higher than that with the resistant strains (99.2% vs. 66.7%, p = 0.045). Moreover, the eradication rate with the levofloxacin susceptible strains in the LCLA group was significantly higher than that with the resistant strains (95.3% vs. 80.0%, p = 0.013). CONCLUSION: Antofloxacin is safe and effective for H. pylori eradication. Antofloxacin-based bismuth quadruple therapy could be an alternative treatment for H. pylori eradication.

Pharmacokinetics of antofloxacin hydrochloride, a novel fluoroquinolone, after single-dose intravenous administration in healthy Chinese male volunteers.

The purpose of the study was to evaluate the pharmacokinetic characteristics of a single, intravenous dose of antofloxacin hydrochloride in healthy Chinese male volunteers. Twelve subjects were randomly assigned to groups that received a single, intravenous dose of 200, 300, or 400 mg antofloxacin hydrochloride in a three-way crossover design study. The serum and urine concentrations of antofloxacin were then assayed with high-performance liquid chromatography (HPLC). Major pharmacokinetic parameters and urine excretion were obtained up to 96 h after administration. All three dosages were well tolerated. No clinically adverse reactions or abnormal laboratory results were detected. After single-dose intravenous administration, antofloxacin hydrochloride exhibited linear pharmacokinetic characteristics with increasing dosages. The C(max) for groups treated with 200, 300, or 400 mg dosages were 2.05 +/- 0.38, 3.01 +/- 0.60, and 3.80 +/- 0.78 mg l(-1), respectively; the areas under the curve from zero to infinity (AUC(0-infinity)) were 25.14 +/- 2.95, 37.63 +/- 5.42, and 53.87 +/- 9.48 mg l(-1).h, respectively. The t(1/2)(beta) was around 20 h; and the urinary excretion was measured as being from 58% to 60% within 96 h. Based on these results, 300 mg of antofloxacin hydrochloride administered once daily is the dose suggested for further investigation in multiple-dose administration studies.

A phase II study of antofloxacin hydrochloride, a novel fluoroquinolone, for the treatment of acute bacterial infections.

AIMS: To evaluate the clinical and bacterial efficacies and the safety of antofloxacin hydrochloride tablets in the treatment of acute exacerbations of chronic bronchitis (AECB) and acute pyelonephritis (AP). PATIENTS AND METHODS: A randomized, controlled, multicenter, double-blind, double-dummy clinical trial was conducted at 6 hospitals in China. The patients in the investigational group took an oral 400-mg loading dose of antofloxacin on the first day followed by 200 mg daily. Control group patients took 200 mg of levofloxacin orally twice daily for 7-14 days. RESULTS: A total of 284 patients were enrolled into the study, including 140 cases of AECB and 144 cases of AP; 141 patients were in the antofloxacin group and 143 patients were in the levofloxacin group. Two hundred fifty-four patients completed the entire treatment and follow-up and comprised the per-protocol analysis data set; 30 patients were excluded because of informed consent withdrawal, loss to follow-up, protocol violations, or adverse drug events. Treatment was ceased in 3 patients in the antofloxacin group and in 1 patient in the levofloxacin group because of skin rashes, dizziness, or adverse gastrointestinal effects. At the end of the 2-regimen treatment, the observed effectiveness rates for AECB were 90.3 and 87.7% for the treatment and control groups, respectively, and 96.9 and 92.1% for AP. The overall bacterial eradication rates were 95.9 and 92.4%, and drug-related adverse events were observed in 13.1 and 10.1% of patients, respectively. There were no severe adverse effects. No statistical differences in drug efficacy and safety were detected between the 2 treatment groups (p > 0.05). CONCLUSIONS: Antofloxacin hydrochloride is an effective and well-tolerated new fluoroquinolone that demonstrates clinical and bacteriological efficacies similar to levofloxacin for the treatment of AECB and AP.

Relationship between antofloxacin concentration and QT prolongation and estimation of the possible false-positive rate.

PURPOSE: To elucidate the relationship between antofloxacin (AT) plasma concentration and QT interval prolongation, compare the effects of different correction and analytical methods on conclusions, and estimate the possible false-positive rate in thorough QT (TQT) studies. METHODS: Twenty-four healthy Chinese volunteers from a four-period crossover TQT study orally received 200 mg/d AT, 400 mg/d AT, 400 mg/d moxifloxacin, and a placebo in a random order for 5 d for each. QT interval samples were collected on d 1 and d 5. Population models were established describing the relationship between QT and AT concentration. The yardstick from ICH E14 guidelines was used to measure the effect of drugs on QT prolongation both in biostatistical and modeling analyses. A possible false-positive rate was estimated by constructing a 1000-time bootstrap to obtain the rate-of-difference values between d 1 and d 5 over 5 ms in the placebo period. RESULTS: In the modeling analysis, the QT prolongation estimate at the mean maximal concentration of AT (4.51 µg/mL) was 3.84 ms, and its upper bound of the one-sided 95 % CI was 7.04 ms, which showed a negative effect on QT interval prolongation. The estimation for the false-positive rate was 31 % in this study. CONCLUSION: The effect of AT on QT interval prolongation may not have been significant at the dosage of 400 mg. Baseline and placebo adjustments were necessary in TQT studies. Population modeling has demonstrated clear superiority in making full use of data to accurately analyze the relationship between drugs and QT intervals.

Mechanism-based inhibition of CYP1A2 by antofloxacin, an 8-NH2 derivative of levofloxacin in rats.

A recent focus was to investigate whether antofloxacin, an 8-NH(2) derivative of levofloxacin, inhibited cytochrome P450 (CYP) 1A2 activity in rats. Phenacetin, the representative substrate of CYP1A2, was used as the model drug to evaluate the activity of CYP1A2. In an in vivo study, an oral single dose of antofloxacin (20 mg kg(-1)) did not affect the pharmacokinetic behaviour of phenacetin, but a multidose (20 mg kg(-1) twice daily for 7.5 days) significantly increased phenacetin's area under the curve (AUC). In an in vitro study, only when pre-incubated with beta-nicotinamide adenine dinucleotide phosphate, a reduced form (NADPH) system in rat liver microsomes, did antofloxacin inhibit phenacetin O-deethylation. The inhibition was NADPH-, pre-incubation time-, and antofloxacin concentration-dependent. A physiologically based pharmacokinetic model with mechanism-based inhibition was successfully developed for predicting the interaction between antofloxacin and phenacetin in vivo from the in vitro data. The simulated AUC was 1.4-fold of the control, which was near the observed value of 1.6-fold. From the results, it can be concluded that the inhibition of CYP1A2 by antofloxacin is mechanism-based.

Pharmacokinetics/pharmacodynamics of antofloxacin hydrochloride in a neutropenic murine thigh model of Staphylococcus aureus infection.

AIM: Antofloxacin hydrochloride is a new fluoroquinolone antibiotic with broad-spectrum in vitro activity. Using the neutropenic murine thigh infection model, we defined the pharmacodynamic profile and property of antofloxacin hydrochloride against Staphylococcus aureus. METHODS: Single-dose pharmacokinetic studies of antofloxacin hydrochloride were carried out in thigh infected mice. Therapy was initiated at 2 h postinoculation with 5-640 mg/kg per d fractionated for different dosing regimens. The thighs were removed for bacterial measurement after 24 h of therapy, the best pharmacokinetic/ pharmacodynamic (PK/PD) index correlated with the efficacy was determined by nonlinear regression analysis. A sigmoid E(max) dose-response model was used to estimate the daily dose and AUC(24 h)/MIC (minimal inhibitory concentration) required to achieve a static effect. RESULTS: The PK was linear with similar elimination half-life over the dose range studied. The AUC(24 h)/MIC ratio was the PK/PD parameter that best correlated with efficacy (R(2)=92.3%, 90.8% for the two organisms, compared with C(max)/MIC and T>MIC [%], respectively). The 24 h static dose ranged from 34.3 to 153.7 mg/kg per d for all S aureus strains, the total AUC(24 h)/MIC ratio to achieve bacteriostatic effect varied from 31.7 to 122.5 (mean, 65.7+/-30.6). CONCLUSION: Antofloxacin hydrochloride showed powerful antibacterial activity against the S aureus isolates used in our neutropenic infected mice model. Our data suggested that the AUC/MIC ratio appeared to be most closely linked to the bacterial outcome (R(2)>90%), and a total AUC(24 h)/MIC ratio of 65.7 appears to be the target value to achieve a net bactericidal activity against S aureus, similar to the results of other fluoroquinolones.

Determination of the inhibitory potential of 6 fluoroquinolones on CYP1A2 and CYP2C9 in human liver microsomes.

AIM: To determine the inhibitory potential of 2 new fluoroquinolones, caderofloxacin and antofloxacin, together with 4 marketed fluoroquinolones, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin, on the activity of cytochrome P450 isoforms 1A2 (CYP1A2) and 2C9 (CYP2C9). METHODS: Probe substrates, phenacetin (CYP1A2), and tolbutamide (CYP2C9) were incubated with human liver microsomes and the metabolites were analyzed by liquid chromatography/mass spectrometry using electrospray ionization in positive or negative mode. Glipizide was used as the internal standard in both modes. The inhibitory potential of fluoroquinolones on CYP1A2 and CYP2C9 was investigated. RESULTS: The IC50 values (micromol/L) determined with the cocktail were in agreement with individual probe substrates (alpha-naphthoflavone: 0.27 vs 0.26; sulfaphenazole: 0.49 vs 0.37). Ciprofloxacin showed weak inhibition on both the activity of CYP1A2 (IC50 135 micromol/L) and CYP2C9 (IC50 180 micromol/L), whereas levofloxacin inhibited only CYP2C9 (IC50 210 micromol/L). Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin showed little or no inhibition on the activity of CYP1A2 or CYP2C9 when tested at comparable concentrations (0-200 mg/L). CONCLUSION: Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin are negligible inhibitors to CYP1A2 and CYP2C9. The in vitro system can be used as a high-throughput model to screen similar compounds for the early identification of drug-drug interaction potential.

Tolerability and pharmacokinetics of antofloxacin hydrochloride after multiple oral dose administration in healthy Chinese male volunteers.

OBJECTIVE: To evaluate the tolerability and pharmacokinetics characteristics of antofloxacin hydrochloride, a fluoroquinolone developed in China, after multiple oral doses in healthy male Chinese volunteers. METHODS: 13 subjects took 300 mg of antofloxacin hydrochloride once daily for 7 days. Safety was evaluated on Days 0, 2, 4 and 8. Blood and urine samples for pharmacokinetics analysis were taken at designated time points. HPLC was used to assay the serum and urine concentration of antofloxacin. RESULTS: A total of 12 subjects completed the trial and 1 volunteer was dropped because of a skin rash 2 h after the drug was administered. 1 volunteer had a prolonged prothrombin time (PT), another had a serum alanine aminotransferase (ALT) elevation and a third had increases in aspartate aminotransferase (AST) and I(3)-glutamyltransferase (I(3)-GT). No other complaints were reported during the trial. The steady state serum concentration on a daily 300 mg oral dose was obtained at 96 h. The pharmacokinetics parameters at steady state were: t(max)1.19 A+/- 0.59 h, C(max) 4.49 A+/- 0.81 mg/l, C(min) 1.35 A+/- 0.33 mg/l, AUC(ss) 74.74 A+/- 12.58 mg/l A h, C(av) 3.11 A+/- 0.52 mg/l, t(1/2beta) 20.75 A+/- 2.93 h, PTF 102.13 A+/- 23.92%. The urinary elimination of antofloxacin over 120 h after the last dose was approximately 62%. C(max) in steady state was 50% higher compared to data for Day 1 after a single dose administration. CONCLUSIONS: The results indicated that 300 mg antofloxacin hydrochloride once daily oral administration is safe, but can lead to high drug concentrations. This should be evaluated further.

The pharmacokinetics of antofloxacin in renally impaired rats.

Our aim was to investigate whether renal impairment induced by cisplatin altered the pharmacokinetics of antofloxacin. Antofloxacin (7.5 mg kg(-1), i.v.) was given to normal or renally impaired rats (induced by cisplatin). Concentrations of antofloxacin in plasma and urine were measured using HPLC. Pharmacokinetic parameters were estimated. The plasma concentrations of antofloxacin in the renally impaired rats were significantly higher than those in the normal rats, accompanied by significant increase of the area under the plasma concentration-time curve (AUC) (968.78+/-259.39 microg min mL(-1) versus 509.84+/-46.19 microg min mL(-1) in normal rats P < 0.05). The system clearance (CL) and renal clearance (CL(R)) of antofloxacin decreased from 12.66+/-1.15 mL kg(-1) min(-1) and 3.21+/-1.80 mL kg(-1) min(-1) in normal rats, to 6.63+/-2.82 mL kg(-1) min(-1) and 0.31+/-0.15 mL kg(-1)min(-1), respectively. No differences between two treatments in half-life and mean residence time were found. We concluded that renal impairment induced by cisplatin significantly altered the pharma-cokinetics of antofloxacin and resulted in decrease of the renal elimination.