[Date of Approval
Date of revision
Androfloxacin Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
[Contraindication
1.Forbidden for those who are allergic to Androfloxacin or quinolones.
2.Forbidden for patients with epilepsy.
3. Contraindicated in pregnant and lactating women, patients under 18 years of age.
4. Contraindicated in patients with underlying arrhythmias or prolonged QT interval, such as severe bradycardia or acute myocardial ischemia.
[Warning].
To reduce the development of bacterial resistance and to maintain the antimicrobial activity of antofloxacin hydrochloride and other antibacterial drugs, treatment with antofloxacin hydrochloride should only be used when bacterial infection is confirmed or highly suspected.
Because the literature on quinolones suggests that QT interval prolongation may cause arrhythmias, this product should be avoided in patients with uncorrectable hypokalemia and in patients receiving antiarrhythmic drugs of classes IA (e.g., quinidine, procainamide) or III (amiodarone, sotalol).
The combination of antofloxacin hydrochloride and drugs that prolong the ECG QT interval (cisapride, erythromycin, antipsychotics and tricyclic antidepressants, etc.) does not exclude a prolonging effect of the QT interval. Therefore, the combination with these drugs should be avoided.
Drug Name
Generic name: Antofloxacin Hydrochloride Tablets
Trade name: Eupen
English name: Antofloxacin Hydrochloride Tablets
Hanyu Pinyin：Yansuan Antuoshaxing Pian
Ingredients
The main component of this product is Antofloxacin Hydrochloride, whose chemical name is: (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-8-amino-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid hydrochloride.
Chemical structure formula.
Molecular formula: C18H21FN4O4-HCl
Molecular weight: 412.8
Properties
This product is film-coated tablets, bright yellow after removing the film coating.
Indications
This product is indicated for the treatment of the following infections caused by sensitive bacteria.
1, acute exacerbation of chronic bronchitis: acute exacerbation of chronic bronchitis caused by Klebsiella pneumoniae.
2, acute pyelonephritis: acute pyelonephritis caused by Escherichia coli.
3, acute cystitis: acute cystitis caused by Escherichia coli.
4, wound infection: wound infection caused by Staphylococcus aureus and coagulase-negative staphylococci.
5, multiple folliculitis: multiple folliculitis caused by Staphylococcus aureus and coagulase-negative staphylococci.
Specification
0.1g (based on C18H21FN4O4).
Dosage]
Take orally. Adults 0.4g once for the first dose and 0.2g once a day for 7~14 days.
When using this product, do not increase the single dose and change the usage.
Adverse reactions]
Based on the use of this product in a total of 493 patients in the completed phase II and phase III clinical trials, the main adverse reactions of Androfloxacin Hydrochloride were mild and moderate (more than 90%). Five patients (1.0%) withdrew from the trial due to adverse reactions, including four cases due to mild adverse reactions such as nausea, dizziness, rash and headache, and one case due to neutropenia. The five patients who withdrew from the trial gradually disappeared after discontinuation of the drug, and the clinical symptoms, signs and laboratory tests returned to normal after one week of discontinuation. No serious adverse events were observed during the entire clinical trial.
According to the summary of the completed phase II and phase III clinical trials of this product, the results of the analysis of common adverse reactions (the drug-related degree is divided into five levels: drug-related, likely drug-related, probably drug-related, not drug-related and not related, of which drug-related, likely drug-related and probably drug-related are calculated as adverse reactions) are listed below according to the number of cases of adverse reactions.
Summary of adverse reactions in phase II and phase III clinical trials
Adverse reactions Androfloxacin group (N=493) Cases occurrence percentage Clinical adverse reactions Digestive system abnormalities Gastric discomfort10 2.03 Nausea9 1.83 Nausea2 0.41 Vomiting1 0.20 Abdominal pain1 0.20 Dry stools1 0.20 Nervous system abnormalities Dizziness9 1.83 Headache4 0.81 Insomnia3 0.61 Drowsiness3 0.61 Vertigo1 0.20 Systemic reactions and others Abnormalities Rash4 0.81 Dry mouth2 0.41 Frequent urination1 0.20 Bilateral lower extremity edema1 0.20 Panic1 0.20 Fatigue1 0.20 Laboratory test abnormalities Elevated alanine transaminase (ALT)7 1.42 Elevated glutamate transaminase (AST)3 0.61 Elevated glutamyl transpeptidase (GGT)3 0.61 Elevated total bilirubin (TBIL)2 0.41 Elevated lactate dehydrogenase ( LDH) elevation1 0.20 Leukopenia1 0.20 Neutrophil reduction1 0.20 Blood glucose elevation1 0.20 ECG abnormalities (premature ventricular beats)1 0.20
Common adverse reactions (incidence ³ 1 % < 10%).
Digestive system: nausea, stomach upset, elevated glutamate transaminase (ALT).
Neurological: dizziness.
Rare adverse reactions (incidence ³ 0.1 % < 1 %).
Systemic reactions: malaise, bilateral lower extremity edema.
Cardiovascular system: cardiac panic, premature ventricular contractions.
Digestive system: dry mouth, poor appetite, vomiting, abdominal pain, dry stools, elevated glutamyl transaminase (AST), elevated glutamyl transpeptidase (GGT), elevated total bilirubin (TBIL).
Urinary system: frequent urination.
Nervous system: headache, insomnia, drowsiness, vertigo.
Skin and adnexa: rash.
hematologic system: leukopenia, decreased neutrophils.
Metabolic and nutritional: elevated blood glucose, elevated lactate dehydrogenase (LDH).
The incidence of these adverse reactions is low and generally well tolerated by patients, with symptoms gradually resolving and returning to normal at the end of treatment. If clinical application of antofloxacin hydrochloride is found to be abnormal, it should be observed, and if necessary, the drug can be stopped and disposed of appropriately.
Contraindications
1. Contraindicated in patients who are allergic to antofloxacin hydrochloride or quinolones.
2.Forbidden for patients with epilepsy.
3.Forbidden for pregnant and lactating women, patients under 18 years old.
4. Contraindicated in patients with underlying arrhythmias or prolonged QT interval, such as severe bradycardia or acute myocardial ischemia.
【Caution】.
1. The effect of antofloxacin hydrochloride on the QT interval of electrocardiogram
A comprehensive QT/QTc phase I clinical study was conducted according to “ICH E14: Guidelines for Clinical Evaluation of QT/QTc Alterations and Rhythm Disorders by Non-Antiarrhythmic Drugs”: A randomized, double-blind, open-ended, four-crossover dosing method was used to evaluate the effects of five consecutive days of antofloxacin hydrochloride tablets on QT/QTc intervals and rhythm in healthy subjects in Chinese volunteers. 12 male and 12 female) were administered 400 mg of antofloxacin hydrochloride, 200 mg of antofloxacin hydrochloride, 400 mg of moxifloxacin and placebo. Each trial was conducted for one week, with 10 days between trials. Electrocardiograms were recorded several times before, during and at the end of administration, three times at each time point; blood samples were also collected to determine blood concentrations for pharmacokinetic analysis; and safety checks were performed according to the protocol. The results showed that QTc prolongation could be induced by both antofloxacin hydrochloride 400 mg and moxifloxacin 400 mg administration, but the QTc prolongation induced by antofloxacin hydrochloride was shorter than that by moxifloxacin and did not reach a dangerous level, and the prolongation of QTc interval in three subjects taking moxifloxacin was beyond the prescribed range. Blood levels at steady-state with 200 mg of antofloxacin hydrochloride had no significant effect on the cardiac QT/QTc interval. Androfloxacin hydrochloride caused QTc prolongation, but not to a dangerous degree, and there was no correlation between its blood concentration and QT interval prolongation.
The results of the conducted phase II and III clinical studies showed that, similar to levofloxacin hydrochloride, no cases of QTc interval prolongation exceeding 60 ms as well as QTc interval exceeding 500 ms were seen, no significant differences in QTc interval compared to baseline, and no significant differences in QTc interval compared to QT interval before and after between and within groups were seen. The literature on quinolones suggests that QT interval prolongation may cause arrhythmias; therefore, this product should be avoided in patients with uncorrectable hypokalemia and in patients receiving antiarrhythmic drugs of class IA (e.g., quinidine, procainamide) or class III (amiodarone, sotalol).
The combination of antofloxacin hydrochloride and drugs that prolong the ECG QT interval (cisapride, erythromycin, antipsychotics and tricyclic antidepressants, etc.) does not exclude a prolonging effect of the QT interval. Therefore, the combination with these drugs should be avoided.
2, renal insufficiency should be used with caution
Due to the lack of pharmacokinetic and pharmacodynamic data on the use of antofloxacin hydrochloride in patients with severe renal impairment, the use of this product in such patients is not recommended.
3. Use with caution in patients with severe hepatic insufficiency
Due to the lack of pharmacokinetic and pharmacodynamic data on the use of antofloxacin hydrochloride in patients with severe hepatic impairment, this product is not recommended for use in such patients.
4. Use with caution in patients with central nervous system disorders
There are reports of convulsions and toxic psychosis after receiving quinolones. Quinolones can increase intracranial pressure and stimulate the central nervous system, resulting in irritability, anxiety, hyperactivity, dizziness, hallucinations and other symptoms, which may occur at the first dose. If a patient has a reaction, the drug should be discontinued immediately, and appropriate therapeutic measures should be taken to seek medical attention promptly.
5.It has been reported that receiving certain quinolones causes peripheral neuropathy and patients feel dullness, fatigue, pain, burning sensation, tingling sensation, numbness and other sensory abnormalities, which should be discontinued immediately after appearing to prevent irreversible conditions.
6. Phototoxic reactions have been reported in patients after receiving certain quinolones. Although this product has been carried out in animal tests and clinical trials, phototoxicity has not been seen at the recommended dose level. However, excessive sunlight or artificial ultraviolet light exposure should be avoided to ensure the successful implementation of medical treatment. If sunburn-like reactions or skin damage occur, prompt medical attention should be sought.
7. Although similar shoulder, hand and Achilles tendon damage caused by other quinolones has not been seen in Phase I, II and III clinical trials, patients should stop using this product if they experience pain, inflammation, tendonitis and/or tendon rupture while receiving this product, and rest and stop physical exercise until tendonitis and/or tendon rupture are clearly excluded. Especially in elderly patients and patients treated with hormones, once tendon pain or inflammation occurs, the patient needs to stop taking the drug and rest the affected limb and seek medical attention as soon as possible.
8. Certain quinolones have been reported to cause hyperglycemic and hypoglycemic adverse reactions, which usually occur in diabetic patients who use oral hypoglycemic agents (such as euglycemia) or insulin in combination. Therefore, it is recommended that these patients should monitor their blood glucose when using this product. If abnormal changes in blood glucose occur, the drug should be discontinued immediately and a medical consultation should be made.
9.If allergy occurs, the drug should be discontinued immediately and treated with the following drugs or methods according to the clinical situation: anaphylaxis can be treated with epinephrine and other resuscitation measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, etc.
10. Pseudomembranous enteritis has been reported after the use of broad-spectrum antimicrobial drugs including quinolones. Therefore, if a patient develops severe diarrhea during treatment with antofloxacin hydrochloride, the possibility of pseudomembranous enteritis should be considered, and the drug should be stopped immediately and appropriate therapeutic measures such as antidiarrheal, intestinal flora adjustment and fluid replacement should be taken.
For Pregnant and Lactating Women
The efficacy and safety of Androfloxacin hydrochloride in pregnant and lactating women have not been established. Therefore, entofloxacin hydrochloride is contraindicated in pregnant and lactating women.
For Children
The efficacy and safety of antofloxacin hydrochloride in children and adolescents have not been established. In animal studies (in young rats), abnormal damage to weight-bearing joints was found with quinolones. Therefore, antofloxacin hydrochloride is contraindicated in patients under 18 years of age.
Geriatric use]
This product is mainly excreted by the kidneys (see “Pharmacokinetics”). Since most elderly patients have low renal function, an increase in blood concentration may occur. Therefore, attention should be paid to the dose of the drug and careful administration.
Drug Interactions]
Drug interaction studies conducted with theophylline have shown that Androfloxacin hydrochloride, similar to other quinolones, inhibits the metabolism of theophylline. Androfloxacin significantly increases the blood concentration of theophylline by about 30%, accompanied by a significant increase in the excretion of the two metabolites of theophylline in urine and an increase in the excretion of theophylline. The effect of single dose of antofloxacin on theophylline was small, while multiple doses showed a strong inhibitory effect, suggesting that antofloxacin may be a mechanistic inhibitor of theophylline metabolizing enzymes. Therefore, clinical co-administration should be avoided as much as possible. If concomitant application is required, the blood concentration of theophylline should be monitored and the dose should be adjusted accordingly.
Considering the reports of possible interactions of quinolones with magnesium or aluminum preparations, steroidal anti-inflammatory drugs, etc., drug interactions with concomitant use of this product with antacids containing magnesium or aluminum, aluminum thioglycollate, metal cations (e.g. iron), zinc-containing multivitamin preparations, warfarin or its derivatives, non-steroidal anti-inflammatory drugs, oral hypoglycemic agents, cyclosporine, digoxin, and probenecid have not been studies. Therefore, try to avoid the combination in clinical practice.
Drug overdose]
No drug overdose studies have been conducted, but the following symptoms may occur with quinolone overdose: nausea, vomiting, stomach pain, heartburn, diarrhea, thirst, stomatitis, hobbling, dizziness, headache, general lethargy, numbness, chills, fever, extrapyramidal symptoms, euphoria, hallucinations, convulsions, delirium, cerebellar ataxia, increased intracranial pressure (headache, vomiting, bruised papillae symptoms), metabolic acidosis, increased blood glucose, increased ALT/AST/ALP, leukopenia, increased eosinophils, thrombocytopenia, hemolytic anemia, hematuria, cartilage/joint disorders, cataracts, visual disturbances, abnormal color vision, and diplopia. In case of overdose of Androfloxacin Hydrochloride, the following first aid measures and antidotes should be taken according to the patient’s condition.
(1)
Gastric lavage.
(2)
Adsorption medicine: activated carbon (40-60g with 200ml of water for oral administration).
(3)
laxatives: magnesium sulfate (30g with 200ml of water), or other slow laxatives.
(4)
infusion (plus liver-protective drugs): metabolic acidosis given by sodium bicarbonate injection, urinary alkalosis given by sodium bicarbonate injection to increase the excretion of this product by the kidneys.
(5)
Forced diuresis: administration of furanophenylephrine injection.
(6)
Symptomatic treatment: sedative drugs such as Valium should be given in case of convulsions.
[Clinical trials
(I) Phase I tolerability trial
A single dose tolerance test of antofloxacin hydrochloride was conducted in 36 subjects, including 6 in the 50 mg group, 8 in the 100 mg group, 8 in the 200 mg group, 8 in the 400 mg group, and 6 in the 500 mg group. The results of the study showed that all the subjects tolerated antofloxacin hydrochloride well, the subjects did not have any complaints of discomfort, no allergic or photosensitivity reactions, most of the indicators of blood and urine routine and biochemical examination were within the normal range, although some indicators were outside the normal range, but had no clinical significance, and all the EEG results were normal. The ECG results showed that one subject in the 200 mg group had prolonged QT interval (536 ms) and mildly prolonged QTc (474 ms) 6 hours after the drug, which returned to normal 24 hours after the drug was administered, considering that the prolonged QTc in this case was related to the drug, and the ECGs of other subjects (including the high-dose 500 mg group) were normal.
(II) Phase II clinical trial
The phase II clinical trial was designed as a multicenter, randomized, double-blind, double-modeled, parallel-controlled trial, with the first dose of 0.4g of antofloxacin hydrochloride tablets and the next 0.2g once a day for 7 to 14 days. In the phase II clinical trial, 288 cases were planned to be enrolled, 284 cases were actually enrolled, of which 126 cases were completed in the antofloxacin hydrochloride group (group A), 14 cases were not enrolled in the PPS, 1 case was excluded, 140 cases were in the FAS population, 126 cases were in the PPS population, 137 cases were in the SS population; 128 cases were completed in the levofloxacin group (group B), 14 cases were not enrolled in the PPS, 1 case was excluded, 142 cases were in the FAS population, 142 cases were in the PPS population, 1 case was in the SS population. The FAS population was 142 cases, the PPS population was 128 cases, and the SS population was 140 cases.
1. Validity results
There were no statistical differences between patients in the test and control groups in terms of general information (gender, age, disease type, condition, underlying disease and duration of treatment, etc.); the baseline balance between the two groups was good and comparable.
(1) Overall validity
The investigators conducted clinical evaluation and statistical analysis of clinical efficacy, bacteriological efficacy and overall efficacy of all cases, AECB and pyelonephritis 1 day after the end of treatment and 7 days after the end of treatment, with the following specific results: clinical cure rates of 60.7% and 55.6% for the FAS population in the antofloxacin hydrochloride group and levofloxacin hydrochloride group 1 day after the end of treatment, respectively, and clinical cure rates for the PPS population The bacteriological clearance rates were 88.7% and 86.8% in the FAS group and 95.9% and 92.5% in the PPS group, respectively; the overall curative cure rates were 62.3% and 54.4% in the FAS group and 67.0% and 58.5% in the PPS group, respectively. The clinical cure rates at 7 days after treatment were 67.1% and 65.5% for the FAS population and 73.8% and 71.1% for the PPS population, respectively; the bacteriological clearance rates were 89.6% and 89.5% for the FAS population and 95.9% and 94.3% for the PPS population, respectively. The overall cure rates were 70.8% and 65.8% for the FAS population and 76.3% and 69.8% for the PPS population, respectively. There was no statistically significant difference (P>0.05) in the comparison of the above results between groups.
(2) Effectiveness of each disease
(1) Treatment of acute exacerbation of chronic bronchitis (AECB).
Sixty-eight cases in the antofloxacin hydrochloride group and 70 cases in the levofloxacin hydrochloride group entered the FAS population; 62 cases in the antofloxacin hydrochloride group and 66 cases in the levofloxacin hydrochloride group entered the PPS population. The clinical cure rates at 1 day after the end of treatment were 47.1% and 41.4% in the FAS group and 50.0% and 43.9% in the PPS group, respectively; the bacteriological cure rates were 45.7% and 37.3% in the FAS group and 46.5% and 38.0% in the PP group, respectively; and the bacteriological cure rates in the FAS group and levofloxacin hydrochloride group, respectively. The bacteriological clearance rates were 91.3% and 94.1% for the FAS population and 95.3% and 94.0% for the PPS population, respectively, and the bacteriological clearance rates for Klebsiella pneumoniae, the main clinical pathogen, were 100% and 91.7%, respectively; the combined efficacy cure rates were 45.7% and 37.3% for the FAS population and 45.7% and 37.3% for the PPS population, respectively. The combined efficacy recovery rates of the two groups were 45.7% and 37.3% for the FAS population and 46.5% and 38.0% for the PPS population, respectively.
② Treatment of pyelonephritis.
There were 72 cases in both the antofloxacin hydrochloride and levofloxacin hydrochloride groups into the FAS population; 64 cases in the antofloxacin hydrochloride group and 62 cases in the levofloxacin hydrochloride group into the PPS population. The clinical cure rates at 1 day after treatment were 73.6% and 69.4% for the FAS group and 82.8% and 79.0% for the PPS group in the antofloxacin hydrochloride and levofloxacin hydrochloride groups, respectively; the bacteriological cure rates were 76.7% and 68.3% for the FAS group and 85.2% and 76.8% for the PPS group, respectively; the bacteriological cure rates for the FAS and levofloxacin hydrochloride groups were 76.7% and 68.3% for the PPS group, respectively. The bacteriological clearance rates were 91.3% and 94.1% for the FAS population and 95.3% and 94.0% for the PPS population, respectively, and the bacteriological clearance rates for Escherichia coli, the main clinical pathogen, were 100% and 90.9%, respectively; the combined efficacy recovery rates were 86.7% and 81.0% for the FAS population and 81.0% for the PP population, respectively. The combined efficacy recovery rates were 86.7% and 81.0% for the FAS population and 96.3% and 91.1% for the PP population, respectively.
In terms of specific disease analysis, the results of non-inferiority analysis (FAS and PPS) of clinical cure rate, bacterial clearance rate and overall efficacy cure rate at 1 day after the end of treatment for AECB cases in the antofloxacin hydrochloride and levofloxacin hydrochloride groups showed that the efficacy of antofloxacin hydrochloride was non-inferior to that of levofloxacin hydrochloride, i.e., the clinical efficacy of antofloxacin hydrochloride for AECB was not inferior to that of levofloxacin hydrochloride. The clinical cure rate, bacterial clearance rate and overall efficacy cure rate at 7 days after treatment could not be concluded that the efficacy of antofloxacin hydrochloride was not inferior to that of levofloxacin hydrochloride, the positive control drug. For the non-inferiority analysis of clinical cure rate, bacterial clearance rate and overall efficacy cure rate at 1 day after the end of treatment and 7 days after the end of treatment for the cases of pyelonephritis in the antofloxacin hydrochloride and levofloxacin hydrochloride groups, the efficacy of antofloxacin hydrochloride was non-inferior to that of the positive control drug levofloxacin hydrochloride, i.e., the efficacy of antofloxacin hydrochloride in the treatment of acute pyelonephritis was not inferior to that of levofloxacin hydrochloride in clinical practice.
2. Safety results
(1) Symptoms and signs
There were 22 cases of drug-related clinical adverse events in the test group, 16 cases of mild, 4 cases of moderate, and 2 cases of severe, in the order of nausea, vomiting, poor appetite, abdominal pain, headache, dizziness, vertigo, tinnitus, insomnia, urinary frequency, rash, skin pruritus, bilateral lower limb edema, and weakness, with an incidence (in terms of number of cases) of 16.06%. In the control group, there were 8 cases of drug-related clinical adverse events, 6 mild, 2 moderate and 0 severe, with basically similar manifestations, and the incidence (in terms of number of cases) was 5.71%.
(2) Laboratory tests
There were 13 cases of drug-related laboratory abnormalities in the antofloxacin hydrochloride group, 11 cases were mild, 2 cases were moderate, and 0 cases were severe, in the order of ALT elevation, AST elevation, LDH elevation, TBIL elevation, GGT elevation, leukopenia, eosinophilia, and ventricular premature. There were 13 cases of drug-related laboratory abnormalities in the levofloxacin hydrochloride group, 11 mild, 2 moderate and 0 severe, with an incidence (in terms of number of cases) of 9.49%. There were 12 drug-related laboratory abnormal adverse events in the levofloxacin hydrochloride group, 11 mild, 1 moderate, and 0 severe, with essentially similar presentations, but no ventricular prematureness was seen.
QTc interval
In this trial, QTc interval was calculated by using Bazett’s correction formula, generally measuring 6 cardiac cycles and averaging them, and after measuring QT, QTc was calculated according to Bazett’s formula (QTc=QT/R-square root of R.) No significant difference was found between QTc interval and QT interval on day 1 and 7 after treatment compared with baseline, and QTc interval was compared with QT interval between and within groups. No significant differences were also seen in pre-post comparisons.
A total of 4 cases withdrew from the trial due to adverse events, including 1 case in the antofloxacin hydrochloride group due to dizziness/nausea, which was likely related; 1 case of skin rash and 1 case of nausea/vertigo (both likely related) discontinued the drug and withdrew from the trial; 1 case in the levofloxacin hydrochloride group discontinued the drug and withdrew from the trial due to skin rash/insomnia (likely related), and all the above 4 patients improved or disappeared after discontinuation of the drug and were not given No special treatment was given. No serious adverse events were reported during the course of this clinical trial.
Effect of blood glucose
In this study, two cases of elevated blood glucose (1.46%) were observed in the antofloxacin hydrochloride group and three cases of elevated blood glucose (2.14%) in the levofloxacin hydrochloride group, all of which were mildly elevated, including four cases of postprandial blood glucose (two cases in the antofloxacin hydrochloride group and two cases in the levofloxacin hydrochloride group), which were judged to be unrelated; one case was judged to be possibly unrelated. No glycemic effects related to the study drug were reported.
The adverse reactions identified during the clinical trial were mainly mild and moderate, with no serious adverse events reported, and there was no statistical difference between the two adverse event groups (P>0.05).
(iii) Phase III clinical trial
The phase III clinical trial was designed using a randomized, double-blind, double-model, multicenter, parallel-controlled clinical trial to evaluate the safety and efficacy of Androfloxacin Hydrochloride Tablets and the control drug Levofloxacin Hydrochloride Tablets in the treatment of acute bacterial infections including respiratory system infections, urinary system infections, and skin soft tissue infections. The main observation and evaluation indexes include: clinical efficacy, bacteriological efficacy, comprehensive efficacy and clinical adverse reactions and laboratory abnormalities. The dosing method was 0.4g for the first time in the antofloxacin hydrochloride group and 0.2g once a day for 7-14 days in the subsequent groups, and 0.2g twice a day for 7-14 days in the levofloxacin hydrochloride group.
A total of 719 cases were enrolled in the phase III clinical trial of this product, among which 360 cases were enrolled in levofloxacin hydrochloride group (group A) and 2 cases were excluded; 358 cases entered the full analysis set (FAS), 341 cases entered the conforming protocol set (PPS) and 358 cases entered the safety set (SS). The antofloxacin hydrochloride group (group B) enrolled 359 cases and excluded 1 case; 358 cases entered the full analysis set (FAS), 330 cases entered the conforming protocol set (PPS), and 356 cases entered the safety set (SS).
For respiratory infections, 239 cases were enrolled in this trial, of which 120 cases were enrolled in the levofloxacin hydrochloride group, 5 cases were not in the PPS set, and 1 case was excluded; 119 cases were enrolled in the antofloxacin hydrochloride group, 11 cases were not in the PPS set, and no cases were excluded. A total of 222 cases were included in the PPS set analysis, including 114 cases in the levofloxacin hydrochloride group and 108 cases in the antofloxacin hydrochloride group; a total of 238 cases were included in the FAS analysis, including 119 cases in both the levofloxacin hydrochloride group and the antofloxacin hydrochloride group; a total of 236 cases were included in the SS analysis, including 119 cases in the levofloxacin hydrochloride group and 117 cases in the antofloxacin hydrochloride group.
For urinary tract infections, a total of 240 cases were enrolled in this trial, including 120 cases in the levofloxacin hydrochloride group, 8 cases not included in the PPS set and 1 case excluded; 120 cases in the antofloxacin hydrochloride group, 9 cases not included in the PPS set and no excluded cases. A total of 222 cases were included in the PPS set analysis, including 111 cases in the levofloxacin hydrochloride group and 111 cases in the antofloxacin hydrochloride group; 239 cases were included in the FAS analysis, including 119 cases in the levofloxacin hydrochloride group and 120 cases in the antofloxacin hydrochloride group; 238 cases were included in the SS analysis, with 119 cases in both the levofloxacin hydrochloride group and the antofloxacin hydrochloride group.
For skin soft tissue infections, 239 cases were enrolled in this trial, including 120 cases in the levofloxacin hydrochloride group and 4 cases not included in the PPS set; 119 cases in the antofloxacin hydrochloride group and 8 cases not included in the PPS set. A total of 227 cases were included in the PPS set analysis in this trial, including 116 cases in the levofloxacin hydrochloride group and 111 cases in the antofloxacin hydrochloride group; a total of 239 cases were included in the FAS analysis, including 120 cases in the levofloxacin hydrochloride group and 119 cases in the antofloxacin hydrochloride group.
1. Validity results
The phase III clinical trial was conducted on the basis of the phase II clinical trial of this product. Inpatients and outpatients with moderate respiratory tract infections, urinary tract infections and skin (including skin soft tissue) infections were used as subjects, and clinical efficacy, bacteriological efficacy and comprehensive efficacy analyses were performed sequentially according to the major disease types on the basis of the results of pharmacodynamic, PK/PD studies and phase II clinical trials of this product. Respiratory system infections were analyzed for pneumonia, acute exacerbation of chronic bronchitis, and acute bronchitis, which had the highest number of enrolled cases; urinary system infections were analyzed for acute pyelonephritis and acute cystitis; skin infections were analyzed for wound infections and multiple folliculitis.
(1) Overall efficacy.
The overall effectiveness of treating acute bacterial infections including respiratory system infections, urinary system infections, and skin soft tissue infections: 1 day after the end of treatment, the clinical cure rates of the FAS population in the antofloxacin hydrochloride and levofloxacin hydrochloride groups were 77.9% and 76.5%, respectively, and the clinical cure rates of the PPS population were 81.5% and 78.0%, respectively; the bacteriological clearance rates of the FAS population in the two groups At 7 days after treatment, the clinical cure rates were 83.5% and 84.4% in the FAS group and 86.7% and 86.2% in the PPS group, respectively; the bacteriological clearance rates in the FAS group and levofloxacin hydrochloride group were 96.8% and 96.4%, respectively. The bacteriological clearance rates were 96.8% and 97.3% for the FAS population and 97.5% and 98.8% for the PPS population, respectively. The statistical analysis of the above results showed no significant difference (P>0.05).
(2) Efficacy of each disease type
The observed results for each disease type are shown in Tables 1, 2 and 3.
Table 1. Clinical summary table of respiratory tract infections 1 day after the end of treatment
Disease type/efficacy FAS PPS Levofloxacin hydrochloride group Androfloxacin hydrochloride group Levofloxacin hydrochloride group Androfloxacin hydrochloride group N Efficacy n(%) N Efficacy
n(%) N Efficacy n(%) N Efficacy n(%) Pneumonia
Clinical efficacy: clinical cure rate 17 7(41.2)14 11(78.6)16 7(43.8)14 11(78.6) Bacteriological efficacy: overall clearance 8 7/8 5 5/5 7 7/7 5 5/5 Klebsiella pneumoniae 6 6/6 22/2 6 6/6 2 2/2 Combined efficacy: cure rate 8 3/8 5 4/5 7 3/7 5 4/5 Chronic bronchitis acute Onset Clinical efficacy: clinical cure rate17 10(58.8)14 9(64.3)17 10(58.8)13 9(69.2) Bacteriological efficacy: overall clearance rate 14 13(92.9) 13 13(100) 14 13(92.9) 12 12(100) Klebsiella pneumoniae5 4/5 3 3/3 5 4/5 3 3 3/3 Combined efficacy: cure rate 14 9(64.3)13 8(61.5)14 9(64.3)12 8(66.7) Acute bronchitis Clinical efficacy: clinical cure rate 62 54(87.1)73 57(78.1)60 54(90.0)64 56(87.5) Bacteriological efficacy: overall clearance 19 19(100) 34 33(97.1) 19 19(100 ) 32 31(96.9) Klebsiella pneumoniae7 7/7 12 12(100) 77/7 12 12(100) Haemophilus influenzae3 3/3 9 8/9 3 3/3 7 6/7 Streptococcus pneumoniae3 3/3 5 5/5 3 3/3 5 5/5 Overall efficacy: clearance rate19 18(94.7) 34 26(76.5) 19 18(94.7) 32 26( 81.3) N: number of evaluable cases or bacterial isolation; n: number of cured or healed cases or bacterial clearance.
Table 2. clinical summary table of urinary tract infections 1 day after the end of treatment
Disease type/efficacy FAS PPS Levofloxacin hydrochloride group Androfloxacin hydrochloride group Levofloxacin hydrochloride group Androfloxacin hydrochloride group N Efficacy n(%) N Efficacy
n(%) N Efficacy n(%) N Efficacy n(%) Acute pyelonephritis Clinical efficacy: clinical cure rate 64 52(81.3)67 54(80.6)59 50(84.7)63 51(81.0) Bacteriological efficacy: overall clearance 56 54(96.4)51 50(98.0)52 51(98.1) 48 47(97.9) Escherichia coli 30 29(96.7) 25 24(96.0) 27 27(100) 23 22(95.7) Overall efficacy: cure rate 56 45(80.4)51 42(82.4)52 43(82.7)48 39(81.3) Acute cystitis Clinical efficacy: clinical cure rate 47 43(91.5)47 42(89.4)45 42( 93.3)43 40(93.0) Bacteriologic efficacy: overall clearance 28 27(96.4) 27 27(100) 26 26(100) 25 25(100) Escherichia coli 15 14(93.3) 15 15 15(100) 13 13(100) 12 12(100) Overall efficacy: cure rate 28 24(85.7)27 24( 88.9)26 23(88.5)25 22(88.0) Table 3. Clinical summary of skin soft tissue infections 1 day after the end of treatment Table
Disease type/efficacy FAS PPS Levofloxacin hydrochloride group Androfloxacin hydrochloride group Levofloxacin hydrochloride group Androfloxacin hydrochloride group N Efficacy n(%) N Efficacy
n(%) N Efficacy n(%) N Efficacy n(%) Wound infection Clinical efficacy: clinical cure rate 20 16(80.0)13 12(92.3)18 15(83.3)13 12(92.3) Bacteriological efficacy: overall clearance 18 17(94.4) 12 12 12(100) 16 16(100) 12 12(100) Staphylococcus aureus 10 10(100) 10 10(100) 9 9(100) 10 10(100) Overall efficacy: cure rate 18 14(77.8) 12 12(100) 16 13(81.3) 12 12(100) Polypoidal folliculitis Clinical efficacy: clinical cure rate 54 35(64.8) 60 39(65.0) 54 35(64.8) 57 37( 64.9) Bacteriologic efficacy: overall clearance 50 49(98.0) 55 55(100) 50 49(98.0) 54 54(100) Staphylococcus aureus 19 18(94.7) 20 20(100) 19 18(94.7) 20 20(100) Coagulase-negative staphylococci 15 15(100) 14 14(100) 15 15 (100) 14 14 (100) Overall outcome: recovery rate 50 32 (64.0) 55 36 (65.5) 50 32 (64.0) 54 35 (64.8)
The number of cases enrolled in pneumonia was small, and only 5 cases could be evaluated for comprehensive efficacy. The current clinical efficacy does not yet indicate the effectiveness for this disease. Acute exacerbation of chronic bronchitis, 12 cases can be evaluated for comprehensive efficacy, and the results of the study can initially confirm the effectiveness of antofloxacin hydrochloride in the treatment of chronic bronchitis caused by Klebsiella pneumoniae. The results of 32 cases of acute bronchitis, which could be evaluated for comprehensive efficacy, showed that antofloxacin hydrochloride was as clinically effective as levofloxacin hydrochloride in the treatment of acute bronchitis caused by Klebsiella pneumoniae, Haemophilus influenzae and Streptococcus pneumoniae. However, it is not included in the indication based on the fact that it is mainly caused by rhinovirus, influenza virus, adenovirus, respiratory syncytial virus, and occasionally by Mycoplasma pneumoniae, Chlamydia pneumoniae, or Bordetella pertussis.
Androfloxacin hydrochloride and levofloxacin hydrochloride for the treatment of acute pyelonephritis as well as acute cystitis were similar in efficacy, with better therapeutic results in terms of clinical efficacy, bacteriological efficacy, and overall efficacy. Better clearance of Escherichia coli, the main clinical pathogen, was achieved. The results of the non-inferiority analysis for the above-mentioned diseases showed that for acute cystitis, the PPS set could not be concluded to be non-inferior to the control drug for the combined efficacy at 1 day after the end of treatment, but could be concluded to be non-inferior to the control drug for the combined efficacy at 7 days after the end of treatment; for acute pyelonephritis, the combined efficacy at 1 day and 7 days after the end of treatment was non-inferior to the levofloxacin hydrochloride group.
Androfloxacin hydrochloride and levofloxacin hydrochloride were effective in the treatment of wound infections and multiple folliculitis caused by Staphylococcus aureus and coagulase-negative staphylococci. The clinical efficacy and overall efficacy of treatment of acute multiple folliculitis was elevated 7 days after treatment compared to 1 day after the end of treatment. The results of the non-inferiority analysis of the above-mentioned diseases showed that the efficacy of the antofloxacin hydrochloride group was non-inferior to that of the levofloxacin hydrochloride group for wound infection and multiple folliculitis.
2. Safety results
A total of 714 cases entered the safety evaluation in the whole group of this study, 358 cases in the levofloxacin hydrochloride group and 356 cases in the antofloxacin hydrochloride group. A total of 38 cases (10.61%) of 358 cases in the levofloxacin hydrochloride group had 48 cases (13.41%) of adverse events, 33 cases (9.2%) 43 cases (12.01%) of adverse events related to the study drug, and 2 cases (0.56%) 5 cases (1.4%) of adverse events leading to case shedding. In the 356 cases in the antofloxacin hydrochloride group, there were 36 (10.11%) cases with 47 (14.04%) adverse events, 29 (8.1%) 38 (10.67%) adverse events related to the study drug, and 2 (0.56%) 3 (0.84%) adverse events leading to case shedding. The degree of adverse reactions was mostly mild and moderate, which resolved and improved with continued use or discontinuation of the drug. The incidence of adverse reactions was similar in both groups, and the incidence of adverse events, and drug-related adverse events in both groups did not differ by statistical tests (P> 0.05).
This study focused on a detailed analysis of the QT/QTc issue in safety. During case approval, seven cases with prolonged QT intervals from previous machine readings were specifically approved. Subjects 482 and 586 did not undergo ECG evaluation of endpoints and were evaluated as normal ECGs according to the data from the previous observation point. The remaining phase III clinical cases were not found to have significantly prolonged ECG QTc after manual measurement by a cardiovascular specialist.
[Pharmacology and Toxicology].
Pharmacological effects
1. Antibacterial mechanism of action
This product is a structurally modified fluoroquinolone antibacterial drug of levofloxacin. The main mechanism of action of levofloxacin is to inhibit the activity of bacterial DNA rotase (bacterial topoisomerase II) and prevent the replication of bacterial DNA to achieve antibacterial effect.
2. Antibacterial activity
The antibacterial test results show that it has antibacterial activity against most of the gram-negative and gram-positive bacteria. In vitro tests have shown antibacterial activity against Gram-positive, Gram-negative, anaerobic and acid-resistant bacteria, as well as atypical pathogenic bacteria such as Mycoplasma, Chlamydia and Legionella.
Antofloxacin has antibacterial activity against Gram-positive aerobic bacteria including: Staphylococcus aureus (MSSA), Staphylococcus epidermidis (MSSE), Staphylococcus intermedius, Staphylococcus saprophyticus, Group A Streptococcus (Streptococcus pyogenes) and Group B Streptococcus, Streptococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis.
Bacteria with antibacterial activity against gram-negative aerobic bacteria mainly include: Haemophilus influenzae, Haemophilus parainfluenzae, Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Enterobacter agglomerans, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella katamora, Aspergillus spp, Salmonella typhi, Bacillus dysenteriae, Salmonella mucilaginosa, Citrobacter, Bacillus immobilis, Pseudomonas aeruginosa, Prudentis and Pseudomonas aeruginosa, Pseudomonas aeruginosa, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, and gonococcus.
In vitro antibacterial activity study showed that the MIC50 of this product is 2mg/L against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), and it has strong inhibitory activity against Staphylococcus intermedius, Staphylococcus saprophyticus, Group A Streptococcus and Group B Streptococcus. It can inhibit 50% of Escherichia coli (ciprofloxacin-sensitive strain), Bacillus immobilis (ciprofloxacin-sensitive strain), Enterobacter aerogenes, Klebsiella pneumoniae, Proteus mirabilis and Bacillus dysenteriae at a concentration of ≤0.25mg/L. It also has strong antibacterial activity against Haemophilus influenzae, Pseudomonas aeruginosa (ciprofloxacin-susceptible strain), Citrobacter, Prudence and Maltophilus, Bacteroides fragilis, and Gonococcus. The in vitro antibacterial activity of antofloxacin against clinical isolates of pathogenic bacteria is shown in the following table.
In vitro antibacterial activity of antofloxacin against clinical isolates of pathogenic bacteria
Fine bacteria MIC50 (mg/L) MIC90 (mg/L) MICRange (mg/L) Staphylococcus aureus (MSSA) 0.125 1 0.008-1 Staphylococcus aureus (MRSA) 2 8 0.125-16 Staphylococcus epidermidis (MSSE) 0.125 1 0.008-1 Staphylococcus epidermidis (MRSE) 2 32 0.06-32 Staphylococcus intermedius 0.25 2 0.125-2 Staphylococcus saprophyticus 0.06 1 0.015-2 Streptococcus pneumoniae2 16 0.125-16 Group A Streptococcus (Streptococcus pyogenes) 0.25 4 0.125-16 Group B Streptococcus 0.25 4 0.03-64 Enterococcus faecalis1 16 0.25-64 Haemophilus influenzae 0.015 0.125 0.008-0.125 gonococci 0.06 0.125 0.015-0.25 Escherichia coli (CPLX-susceptible strain) 0.252 0.015-2 Escherichia coli (CPLX-resistant strain) 16 64 1->128 Enterobacter cloacae 0.5 64 0.015-128 Enterobacter aerogenes 0.06 0.5 0.06-> ;128 Enterobacter polymorpha 0.06 0.50.06-2 Salmonella typhi 0.125 20.125-4 Dysentery bacilli 0.251 0.008-2 Proteus spp. (CPLX-susceptible strain) 0.125 0.25 0.004-0.5 Proteus spp. (CPLX-resistant strain) 8 16 4-32 Klebsiella pneumoniae 0.06 8 <0.008- 128 Citrobacter32 64 0.25-64 Serratia marcescens0.25 2 0.06-8 Pseudomonas aeruginosa (CPLX-sensitive strain)1 2 2 Pseudomonas aeruginosa (CPLX-resistant strain)8 32 2-32 Bacteroides immobilis spp. (CPLX-sensitive strain)0.03 0.25 0.015-2 Bacteroides immobilis spp. (CPLX-resistant strain)4 16 2-16 Flavobacterium maltophilia Bacillus spp. 0.5 4 0.25-4 Prudence spp. 0.25 1 0.125-1 Candida fragilis 0.5 2 0.125-2 Candida albicans>128 >128 >128 Note: MSSA: methicillin-susceptible Staphylococcus aureus; MRSA: methicillin-resistant Staphylococcus aureus; MSSE: methicillin-susceptible Staphylococcus epidermidis Staphylococcus; MRSE: methicillin-resistant Staphylococcus epidermidis; CPLX: ciprofloxacin.
Bactericidal test shows that this product has significant bactericidal effect at 1/2MIC, MIC, 2MIC, 4MIC concentration; it can kill 99% of bacteria when it works with bacteria for 24 hours.
Toxicological study
1. Acute toxicity
The LD50 of Antofloxacin hydrochloride in mice is 1929 mg/kg at one oral dose, 95% of which is 1,664~22%.
The LD50 for mice is: 215.8 mg/kg, 95%.
The mice mainly showed reduced activity after administration, and no obvious pathological changes were observed in the organs.
In rats, the oral LD50 of Androfloxacin Hydrochloride>3000 mg/kg; the intravenous LD50 of Androfloxacin Hydrochloride>200 mg/kg. the target organs of toxicity may be liver, heart and lung, and there are toxic effects on the gastrointestinal tract when administered orally.
2. Long-term toxicity
(1) Long-term toxicity test in dogs
Dogs were orally administered 8, 24 and 48 mg/kg/day of antofloxacin hydrochloride for 3 months, and then stopped for 1 month to recover. The dogs in each dosing group showed varying degrees of hind limb weakness and generalized tremors after dosing, which showed obvious dose correlation, suggesting that the product had an effect on the neuromuscular system of the animals. Two dogs in the high and medium dose groups each showed mild swelling of the eyelid skin after administration, suggesting that the product may affect the water and salt metabolism of the dogs.
Beagle dogs were given oral doses of antofloxacin 72 mg/kg/day for 3 months. The dogs showed weakness of the hind limbs, lying on the ground and trembling all over the body; puffiness of the skin of the face and both ears; weight gain slowed down and food intake decreased from the 9th week of dosing; heart rate slowed down significantly and ECG QTc interval prolonged significantly compared with that before dosing 3 months after dosing; blood biochemical tests showed that ALT, AST and Crea were elevated and TP and ALB were decreased; hematological tests showed no abnormalities.
The gallbladder of the administered dogs was filled, and a few dark brown sediment-like stones, mesenteric lymph nodes and intestinal mucosa were congested as well as the liver was lighter in color. Pathological histological examination showed that the liver of the drug-administered group showed scattered small focal necrosis of hepatocytes with inflammatory cell infiltration, slightly increased number of binucleated hepatocytes and increased phagocytosis of brownish pigment granules by Kupffer cells; hemorrhage in the medullary sinus of mesenteric lymph nodes. The remaining changes were not clearly drug-related.
The results of toxicokinetic tests performed in the canine long term toxicity test showed that the Cmax and AUC0-24 of the 48 mg/kg group, which did not cause prolongation of the QT interval, were 12.415±2.08 μg/ml and 126.5±21.4 μg.h/ml, respectively, and the Cmax and AUC0-24 of the 72 mg/kg group, which caused prolongation of the QT interval, were 27.54±3.2 μg.h/ml, respectively, after 90 days of continuous administration. 27.54±3.2μg/ml and 245.99±49.9μg.h/ml, respectively.
Pathological sections of sternal osteoarthritic cartilage and long bone knee cartilage of Beagle dogs administered for 90 consecutive days showed no chondrocyte degeneration or matrix loss, and no significant differences were observed compared to the control group.
In the above two toxicity studies in dogs, the main toxicities of this product were: weakness of the hind limbs and puffiness of the skin of the face after administration; prolongation of the QTc interval of the electrocardiogram in Beagle dogs given 72 mg/kg orally for 3 months; impaired liver function and small focal necrosis of hepatocytes on pathological examination. The above results suggest that the main toxic target organs of this product in dogs are heart and liver.
The non-toxic dose of this test was 8mg/kg.
(2) Long-term toxicity in rats
Rats were orally administered with 40, 80 and 160 mg/kg/day of antofloxacin hydrochloride for 3 months, and then stopped for 1 month to recover. Irregular salivation was observed in all dosing groups, and the time and frequency of salivation were significantly correlated with the dose; the salivation disappeared after the drug was stopped. No pathological changes related to the administration of the drug were observed in the blood picture, biochemical and pathological examinations of the rats in all groups. This experiment indicates that this product may have an effect on the vegetative nervous system of rats.
The non-toxic dose for long-term administration to rats is 160mg/kg.
3. Genotoxicity
(1) Cell chromosome aberration test: The IC50 value of the product on cells was used as the maximum concentration, and three concentrations were diluted sequentially in multiples to investigate the aberrant effect of the product on chromosomes of CHL cells in the presence or absence of S9. RESULTS: Under all conditions, the chromosomal aberrations in the medium and low concentration groups were below 5%, and the chromosomal aberrations in the high concentration group (IC50) cells were ³ 5%, indicating the potential induction of chromosomal aberrations in CHL cells by androfloxacin hydrochloride at high doses.
(2) Cytogenetic mutagenesis assay: The mutagenic effect of antoxacin hydrochloride on hypoxanthine guanine transphosphate ribosylase locus (HGPRT) was examined using V79 cell line. Antofloxacin hydrochloride 300 μg/ml did not induce HGPRT gene mutation in V79 cells in the presence or absence of S9.
(3) Bone marrow micronucleus test in mice: mice were orally administered 1.0, 0.5 and 0.25 g/kg of antofloxacin for 2 days, and the effect on micronucleus formation of polychromatic erythrocytes in mouse bone marrow was observed 24 hours after the last dose. The results showed that the product did not induce the formation of polychromatic erythrocyte micronuclei in bone marrow.
The above information suggests that this product may have potential chromosomal teratogenic effects at higher doses.
4. Reproductive toxicity
(1) General reproductive toxicity test: when Androfloxacin hydrochloride was given to male rats during spermatogenesis, female rats during oocyte growth and development and early embryonic stage at doses of 40-320mg/kg/d, it had no significant effect on the reproductive ability of female and male rats.
(2) Teratogenic sensitivity period toxicity study: Androfloxacin hydrochloride was not teratogenic, and the dose of 50mg/kg was a non-toxic dose for pregnant rats and embryonic development.
The oral administration of 40, 80 and 160 mg/kg/day of antofloxacin hydrochloride on days 6-18 of gestation did not show significant teratogenic effects in rabbits. However, the 80 and 160 mg/kg groups showed more severe gastrointestinal reactions to the mother. Under the conditions of this test, antofloxacin hydrochloride had no significant teratogenic effect on rabbits, but had significant toxic effects on pregnant rabbits. 40 mg/kg was the non-toxic dose for this test.
(3) Perinatal reproductive toxicity test: perinatal administration of antoxacin hydrochloride to rats at doses in the range of 40-320 mg/kg/d had no significant effects on the behavior, activity, body weight and embryo of F0 generation females, except for the salivation of some F0 generation females after administration of antoxacin hydrochloride. There was no significant effect on the growth and development of F1 generation rats, lactation survival, physiological development, neurobehavioral ability, motor coordination, swimming exhaustion time, learning and memory ability, autonomous activity, reproductive ability and the survival and growth of F2 generation rats. 320mg/kg was the non-toxic dose for this test.
5. Phototoxicity test
Balb/c mice were orally administered three doses of 50, 100 and 200 mg/kg of antofloxacin hydrochloride for 7 days, and irradiated with ultraviolet light at an intensity of 21.6 J/cm2 per day. Compared with other quinolones, the phototoxicity was significantly lower than that of lomefloxacin, sparfloxacin and ciprofloxacin, and comparable to norfloxacin.
6. Pharmacokinetics
(1) Distribution: Experiments in rats show that Androfloxacin hydrochloride is widely distributed in the body, except for brain and adipose tissue, other tissue concentrations are higher than plasma drug concentrations, with the highest concentrations in the lung, spleen, intestine, stomach and kidney, and higher concentrations in the liver and ovaries.
(2) Metabolism: Experiments in rats showed that high concentrations of glucuronide-binding products were found in bile, suggesting that the metabolite may also be present in human bile.
(3) Plasma protein binding: The plasma protein binding rate of antofloxacin hydrochloride in human plasma was 17.52% as measured by equilibrium dialysis, similar to most quinolones, and antofloxacin hydrochloride is a low protein binding rate drug.
7. Effect on delayed rectifier potassium current (IK) in guinea pig ventricular myocytes: Individual guinea pig ventricular myocytes were digested with collagenase, and the effect of different concentrations of antofloxacin hydrochloride on IK was observed by whole-cell membrane clamp recording method, and the corresponding concentration of levofloxacin lactate was used as a positive control. RESULTS: Androfloxacin hydrochloride inhibited IK currents in a concentration-dependent manner. Levofloxacin also had a concentration-dependent inhibitory effect on IK.
[Pharmacokinetics].
After single oral doses of 300, 400 and 500 mg of Androfloxacin hydrochloride in healthy subjects, the time to peak (Tmax) was measured as 1.09±0.58, 1.40±0.48 and 1.62±0.58 hours, respectively, indicating rapid absorption of the drug, and the peak concentrations (Cmax) were 2.91±0.43, 3.53±0.52 and 4.32±0.10 mg/L, respectively. After oral administration, the blood concentration-time profiles of antofloxacin hydrochloride in humans were in accordance with the characteristics of the two-compartment model, with estimated distribution half-lives (T1/2α) of 7.46±3.44, 7.49±1.91, and 9.77±4.60 hours, respectively, and elimination half-lives (T1/2β) of 20.3±4.35, 20.22±3.33, and 20.61±4.58 hours, respectively. 20.61±4.58 h. Approximately 40-45% of antofloxacin hydrochloride was excreted from the urine in its original form within 72 h of administration. The estimated area under the curve (AUC0-tn) for the three doses were 44.23±6.49, 59.67±12.19, and 80.05±15.79 μg.h/ml, respectively, with a good linear relationship between peak concentration, AUC0-tn and dose. The results of the study showed that the pharmacokinetics of antofloxacin hydrochloride in the dose range of 300-500 mg in humans was in accordance with the linear kinetic characteristics.
The main pharmacokinetic parameters of 300, 400 and 500 mg doses of Androfloxacin Hydrochloride
Results (Mean±SD) Parameters 300mg 400mg 500mg Cmax(mg/L) 2.91±0.433.53±0.524.32±0.10Tmax(h) 1.09±0.581.40±0.481.62±0.58T1/2α(h) 7.46±3.447.49±1.919.77± 4.60T1/2β(h)20.3±4.3520.22±3.3320.61±4.58V/F(L/kg) 2.88±0.563.00±1.072.75±0.86CL/F(L/h/kg) 0.10±0.020.10±0.030.09±0.02AUC0-tn(μg.h/ ml)44.23±6.4959.67±12.1980.05±15.79AUC0-∞(μg.h/ml)51.2±7.2866.6±11.6185.9±16.6272h cumulative excretion%45.63±14.1443.60±17.5440.03±9.98V/F: total apparent volume of distribution ; CL/F: plasma clearance.
Figure 1. Blood concentration-time curves of single oral doses of 300, 400 and 500 mg of Androfloxacin Hydrochloride in healthy subjects
The results of the continuous pharmacokinetic study showed that the blood concentration of antofloxacin hydrochloride reached steady-state on 4 days, and the mean peak concentration after steady-state was 4.49±0.81 mg/L. The steady-state blood concentration (Cav) was 3.11±0.52 mg/L, and the area under the steady-state blood concentration curve (AUCss) was 74.74±12.58 μg.h/ml, and the cumulative urinary drug excretion rate was 61.94% at 120 hours.
Figure 2. Blood concentration-time curve of 300 mg x 7 days of continuous oral administration of antofloxacin hydrochloride in healthy subjects
Blood concentrations reached steady-state levels on day 2 when 200 mg was administered once daily, with the first dose doubled (400 mg). The time to peak blood concentration was 1.5±0.7 hours.
The steady-state peak concentration was 2.10±0.39 mg/L, the trough concentration was 0.53±0.25 mg/L, the fluctuation was 1.6±0.4, the area under the steady-state blood concentration curve was 24.32±6.03 μg.h/ml, and the cumulative percentage excretion in urine at 120 hours was 60.06%.
Figure 3. Blood concentration-time curve of antofloxacin hydrochloride in healthy subjects with first dose of 400 mg and continuous oral dose of 200 mg x 6 days
The pharmacokinetic characteristics of Androfloxacin hydrochloride are as follows.
Absorption.
The results of pharmacokinetic study of single oral doses of 300, 400 and 500 mg of Androfloxacin Hydrochloride tablets in healthy volunteers showed that the peak blood concentration time was 1.09±0.58, 1.40±0.48, 1.62±0.58 hours after oral doses of 300, 400 and 500 mg of Androfloxacin Hydrochloride tablets in 12 subjects in a triple crossover test, respectively, with rapid absorption of the drug and peak concentration After oral administration of androfloxacin, the blood concentration-time curve of androfloxacin in human body was in accordance with the characteristics of the two-atrial chamber model, and the estimated distribution half-lives were 7.46±3.44, 7.49±1.91 and 9.77±4.60 hours, indicating that the drug was distributed slowly in human body and the elimination half-lives of 20.3±4.35, 20.22±3.33, and 20.61±4.58 hours, respectively, indicating that the drug is eliminated relatively slowly in the body. The estimated AUC0-tn of the three doses were 44.23±6.49, 59.67±12.19, 80.05±15.79 μg.h/ml
, with a good linear relationship between peak concentration, AUC0-tn and dose. In the range of 300-500 mg, antofloxacin conformed to linear kinetics in human body, with a long elimination half-life of about 20 hours, which was longer than that of levofloxacin (6 hours), and the in vivo exposure (AUC) of the same dose of antofloxacin was also higher than that of levofloxacin.
The results of a pharmacokinetic study of continuous administration of 300 mg orally once daily for 7 consecutive days showed that blood concentrations reached steady state at 4 days of administration, with a mean trough concentration of 4.49 ± 0.81 mg/L and a mean peak concentration of 20.75 ± 2.93 mg/L after steady state.
Comparison of pharmacokinetic studies between single and continuous dosing on day 7 showed no difference in half-life between single and multiple dosing, indicating that the in vivo course of the drug was not significantly altered by continuous dosing. The accumulation factor was 1.91±0.77 calculated from the blood trough concentrations on the 1st and 6th days of continuous administration, and the blood concentration reached steady state on the 4th day of continuous administration with a DF (%) of 102.13±23.92 and an accumulation factor of 1.91±0.77, indicating that there was basically no accumulation of antofloxacin hydrochloride in the body.
The results of the pharmacokinetic study of sequential administration of 200 mg orally once daily and doubling of the first dose (400 mg) showed that doubling of the first dose resulted in faster attainment of steady-state blood levels. The time to peak blood concentration was 1.5±0.7 hours, the steady-state peak concentration was 2.10±0.39 μg/ml, the trough concentration was 0.53±0.25 μg/ml, the fluctuation was 1.6±0.4, and the area under the steady-state blood concentration curve was 24.32±6.03 μg.h/ml.
Distribution.
Experiments in rats showed that antofloxacin was widely distributed in vivo, with concentrations higher than plasma drug concentrations in all tissues except brain and adipose tissue, with the highest concentrations in lung, spleen, intestine, stomach and kidney, and higher concentrations in liver and ovary, suggesting that a similar phenomenon may exist in humans. Data from human studies are lacking.
The plasma protein binding rate of antofloxacin in human plasma measured by equilibrium dialysis was 17.52%, which is similar to most quinolones, and antofloxacin is a low protein binding drug. The protein binding rate of antofloxacin in rat plasma was 33%, indicating that there is a species difference.
Metabolism.
After oral administration of antofloxacin in humans, three phase I metabolites were found in human urine, which were initially identified by LC-IT-TOF/MS technique as N-desmethyl antofloxacin, N-oxidized antofloxacin and N-desmethyl antofloxacin hydroxylation products, and no de-NH products were found. No phase II metabolites were found in human urine.
Experiments in rats showed high concentrations of glucuronide-binding products in bile, suggesting that this metabolite may also be present in human bile. Data from human studies are lacking.
Excretion.
Urinary fractions of excretion of protoforms in healthy subjects following single oral doses of 300, 400, and 500 mg of antofloxacin were 45.5%, 43.6%, and 40.3%, respectively, over 72 h. Urinary excretion fractions were similar for the three doses. Assuming a 100% oral bioavailability, 40-60% of the drug was excreted in vivo as a prodrug or/and metabolite in the feces and as a metabolite in the urinary tract.
In rats, only 22% is excreted in its original form and about 80% is eliminated in the metabolic form. Experiments in rats showed that 1.8% of the drug was excreted in the bile and 6.4% in the feces, suggesting that in humans some of the drug may also be excreted in the bile or feces. There is a lack of data from human studies.
Influencing factors.
Gender factors
The results of a pharmacokinetic study of oral administration of 300 mg of antofloxacin hydrochloride in 5 healthy female and 6 male subjects (while evaluating the effect of food on the in vivo course of antofloxacin) showed that subjects who received 300 mg of antofloxacin orally within 30 min of a fast or meal (yogurt: 125 g, 1 meat bun, 1 egg), whether administered with food or on an empty stomach, antofloxacin in male There were no significant differences in the pharmacokinetic parameters in both male and female subjects, suggesting that there are no gender differences in the pharmacokinetic behavior of antofloxacin.
Food factors
The above study on the effect of gender on the pharmacokinetics of the drug also showed that except for a slight delay in the time to peak (P>0.05), there was no significant difference in the pharmacokinetic parameters of the drug when administered after a meal compared to fasting, suggesting that normal eating does not affect the pharmacokinetic behavior of antofloxacin.
Storage
Store under shade and seal.
Package
Double aluminum foil package. 6 tablets/box; 10 tablets/box.
Expiration date
24 months.
Execution Standard
Approval number】
【Manufacturer】
Company Name: Anhui Global Pharmaceutical Co.
Production Address: No. 1185 Huaguang Avenue, Bengbu City
Postal Code: 233010
Telephone number: 0552-4098318
Fax number: 0552-4098962
Web
Address: http//www.ahgp.com.cn