Pharmacokinetics and Bioequivalence Study of Two Ciprooxacin Hydrochloride Tablets in Chinese Healthy Volunteers Under Fasting and Fed Conditions: A Randomized, Open-Label, Two-Formulation, Two-Sequence, Two-Period, Single-Dose Crossover Study.

Background Ciprooxacin is a broad-spectrum uoroquinolone antibiotic which is active against a wide range of Gram-positive and Gram-negative bacteria. The study mainly aimed to determine the bioequivalence of two branded ciprooxacin hydrochloride tablets (250 mg) under the fasting and fed conditions. The study was carried out in 48 healthy Chinese subjects under fasting and fed conditions with a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design. In each period of the study, the subjects were assigned to receive a single oral dose of 250 mg of ciprooxacin hydrochloride. Blood samples were collected from an hour before dosing to 36 h after administration with 16 time points in total. The bioequivalence analysis was performed after ln-transformation of the ciprooxacin pharmacokinetic parameters including maximum concentration (C max ), area under the plasma concentration–time curve from time 0 to time t (AUC 0-t ), area under the plasma concentration-time curve from time 0 to innity (AUC 0- ∞ ). Two formulations are considered bioequivalent if the 90% condence intervals (CIs) for the test/reference geometric mean ratios (GMRs) for the ln-transformed pharmacokinetic parameters fall within the standard acceptance range of 80% – 125%. dilution reliability, residual effect of HPLC injection, analytical batch length, reproducibility for reinjection of 72 hours, placement stability of processed samples, freeze-thaw stability, stability of samples, matrix effects, hemolysis effects, recovery rate, accuracy and precision, reproducibility for reinjection of 72 hours.


Background
Cipro oxacin is a broad-spectrum uoroquinolone antibacterial agent which exhibits excellent antimicrobial activity against a wide range of Gram-negative and Gram-positive bacteria. Cipro oxacin is one of the few broad-spectrum antibacterial agents clinically effective after both oral and intravenous administrations. Like other quinolones, the antibacterial mechanism of cipro oxacin is inhibition of bacterial topoisomerase II that belongs to a DNA gyrase and introduces negative supercoils into bacterial DNA. It is believed that quinolones act on the A subunits of DNA gyrase to inhibit resealing of the DNA double-strand, and promote the exonucleolytic degradation of bacterial single-strand DNA to play a bactericidal role [1][2][3].
Cipro oxacin has a wide range of clinical uses owing to its broad antibacterial spectrum, and is e cacious in the therapy of various infections, especially those caused by Gram-negative pathogens [4].
After a single-dose oral administration of 250-mg cipro oxacin, mean peak serum concentrations of 1.35 to 1.42 ug/ml for cipro oxacin were achieved at 1-1.5 h in a dose-dependent model, the mean value (± SD) for area under the serum curve from 0 to 12 h was 5.43 ± 0.54 h·ug/mL; the terminal serum half-live was in the range of 3.8 to 4.3 h, and the percent of cipro oxacin recovered in urine 0 to 12 h after administration ranged from 30-45% [14]. The mean absolute bioavailability after oral administration of cipro oxacin ranges from 69-85% [1]. Food could delay the absorption of cipro oxacin, but without signi cant impact on pharmacokinetics pro le [15].
Most of drug-related adverse reactions of cipro oxacin are mild to moderate, and the total incidence of adverse drug reactions of cipro oxacin is 10.2%. Cipro oxacin was well-tolerated according to pooled data across worldwide clinical trials consisting of 8861 courses of cipro oxacin, and the most frequently adverse drug reactions involved gastrointestinal symptoms (5%), metabolic and nutritional symptoms (4.6%) [16].
The main objective of this study was to determine the bioequivalence of cipro oxacin hydrochloride formulation manufactured by Baiyunshan Pharmaceutical General Factory (Guangzhou, China) with a branded innovator product after oral administration with single 250-mg dose in healthy Chinese volunteers. We investigated the pharmacokinetic properties and intra-individual variation coe cients of cipro oxacin under fasting and fed conditions by determining the cipro oxacin plasma concentrations. The validation of rationality involved the method of analyzing the cipro oxacin plasma concentrations, and the time interval setting of blood collection time and cleaning period. The secondary object of the study was to evaluate the tolerance and safety of cipro oxacin in healthy volunteers.

Ethics
The study was performed as a randomized, open-label, two-formulation, two-sequence, two-period, singledose crossover bioequivalence study with a wash-out period of 7 days, and conducted at the Guangdong Province Traditional Chinese Medical Hospital, Guangzhou, China. The study was approved by the independent Ethics Committee of the hospital (registration number: A2017-002-1-02) on the basis of the principles of some international guidelines including the CIOMS (Council for International Organizations of Medical Sciences) International Ethical Guidelines for Biomedical Research Involving Human Subjects, the Good Clinical Practice, the World Medical Association's Declaration of Helsinki, and WHO Operational Guidelines for Ethics Committees for Biomedical Research Review. The signed informed consent was acquired from every enrolled volunteer before formal screening.
We chose the cipro oxacin hydrochloride tablet (Ciprobay ® , drug speci cation: 250 mg; purity: 98.4%; batch number: BXN14RC; expiry date: August, 2020) manufactured by Bayer Vital GmbH, Leverkusen, Germany, as the reference product, in accordance with the Procedures for Selection and Determination of Reference Product for Generic Chemicals, which was published by the National Medical Products Administration (NMPA), Beijing, China. The reference product was in the recommended list of NMPA.

Inclusion and Exclusion Criteria
Subjects who met all the following requirements could be included: Subjects aged at least 18 years old, at most 45 years old, with appropriate sex ratio Male subjects weighed ≥ 50 kilogram and female subjects weighed ≥ 45 kilogram, with a body mass index (BMI) between 19-26 kg/m 2 All medical examination results showed no abnormality, or abnormality without clinical signi cance Female subjects with negative pregnancy tests and male subjects had no fertility planning from two weeks before administration to the next six months, they and their partners used effective contraception and had no egg or sperm donation programs Subjects were fully aware of the purpose, nature, methods, and possible adverse events of the study, volunteered to serve as subjects, and signed informed consent before the study began Subjects were able to communicate well with the researchers, and understood and complied with the strict requirements of the study.
Subjects who met any of the following criteria would be excluded: Allergic physique, or allergy to the food and drug, especially for penicillin, clarithromycin, cephalosporin Surgical or medical history, illness with clinical signi cance, which would endanger the safety of subjects or have an impact on study results Di culty for swallowing, or gastrointestinal disease, which affected drug absorption Positive test results for hepatitis B surface antigen (HBsAg), anti-HIV antibodies, hepatitis C antibody, or treponema pallidum antibody Gestation or lactation for the female subjects Diarrhea after drinking milk in fed study Positive urinary drug screen for morphine, methamphetamine, ketamine, dimethylene dioxyamphetamine, tetrahydrocannabinolic acid, cocaine Habitual use of Chinese herbs or functional vitamins Participation in another clinical trials within three months prior to the screening Blood donation or blood loss exceeded 400 mL within three months prior to the screening, or intention to donate blood during the clinical trial within three months after the end of the clinical trial Use of any medication or health products within three months prior to the screening Smoking > 5 cigarettes per day within three months prior to the screening, or disagreement to avoid using any tobacco products during the trial Alcohol drinking averaged > 14 units per week or > 2 units per day within 3 months prior to the screening, 1 unit was equivalent to 17.7 mL ethanol, or disagreement to avoid using any ethanol products during the trial Values for alcohol breath test results were > 0.0mg /100 mL A long history of consuming excess caffeinated beverages, which were more than eight drinks a day, 1 drink was 250 mL, or intake of food or drinks rich in methyl xanthine purines or caffeine (coffee, strong tea, cola, chocolate, etc) within 48 hours prior to the administration, and failure to stop the intake during the clinical trial Intake of special diet, such as pitaya, mango, pomelo, the food and drinks prepared from these fruits, or strenuous exercise within 48 hours prior to the administration, or other factors that could affect the absorption, distribution, metabolism, or excretion of cipro oxacin Intolerableness to venipuncture blood collection or history of dizziness Special requirements for diet, and failure to follow the uniform diet Occurrence of acute illness during the screening period, or before the administration Any other factors the researchers considered inappropriate for volunteers to participate in the study.

Subjects
After signing the informed consent forms, all enrolled volunteers would undergo a series of inquiries and examinations, such as demographic data, medical history, allergy, the history of smoking and drinking, physical examination, weight and height measurement, vital signs, 12-lead electrocardiogram (ECG), chest radiography, laboratory analysis of blood routine, urine routine and blood biochemistry, serum pregnancy test (female only) and disease markers for syphilis, HIV (human immunode ciency virus), and hepatitis B and C viruses. The screening tests were performed within 7 days prior to the rst period of administration.
The volunteers who met all the inclusion criteria and did not meet any of the exclusion criteria during screening period were noti ed to enroll in the Phase Clinical Research Center of the hospital for a uniform lunch and dinner one day before the trial. In the fasting study, a total of 107 volunteers were recruited, 93 of whom were excluded. For the fed study, 26 of 90 volunteers were eligible, among whom 24 volunteers were assigned to receive a randomized order and the remaining 2 volunteers were excluded because the number of subjects had exceeded the predetermined number (24).
The following assessments were performed again before administration: health survey (recent medical history, medication history, smoking and drinking), vital sign measurement, female pregnancy test, alcohol breath test, drug screening in urine. In accordance with these assessments, the researchers checked the inclusion/exclusion criteria again and made the nal decision, and all enrolled subjects must guarantee to fast for at least 10 hours before administration.
Under the terms of the informed consent, the subject had the rights to withdraw from the study and revoke the informed consent without any reason at any time, also without any impact on their rights, interests, and entries into other clinical studies. The researchers would let the subjects withdraw from the study if the subjects were un t to continue the study in the following cases: Necessity to stop the study from the point of view of medical ethics

Occurrence of serious adverse events (SAEs)
Poor compliance involved failure to accept the examination and administration according to regulations, use of drug or food affecting safety assessment and pharmacokinetic analyses Other behaviors that could affect the test results

Study Drug Administration
Subjects were randomly assigned to receive a single oral dose of the test (T) or reference (R) product of cipro oxacin hydrochloride 250 mg, in light of a balanced randomization schedule generated by SAS 9.4 (SAS Institute Inc., Cary, NC, USA), and the study drug was administrated in the order of T-R or R-T during each period.
In the fed study, 24 subjects were randomly assigned to two groups at a 1:1 ratio. After an overnight fast of ≥10 hours. Cipro oxacin hydrochloride tablets were administered with 240 mL of water after standardized high-fat and high-calorie (800-1000 kilocalorie) meals, the meals were eaten up within 30 minutes, and chewing drugs was forbidden during administration. Subjects were granted a free access to water until 1 hour before study drug dosing and 1 hour after administration, and fasted until 4 hours after administration. Standard light meals were provided 4 and 10 hours after administration of cipro oxacin hydrochloride tablets. Two dosing periods were separated by a 7-day washout period, and two groups were cross-administered on the seventh day. For the fasting study, the only difference from the fed study was that subjects fasted until 4 hours after administration.
Vital signs (pulse, blood pressure, body temperature) were assessed prior to dosing and at 2 (± 0.5) h, 4 (± 0.5) h, 12 (± 0.5) h, 24 (± 0.5) h after administration. The assessments should delay until sampling was completed, if there was a scheduling con ict between the assessments and sampling. Adverse events (AEs), concomitant medication usage and non-drug treatments were tracked through the whole study. Subjects were permitted to leave the Phase Clinical Research Center of the hospital until all blood sample collections were completed. Snacks, areca nuts, alcoholic drinks and smoking were forbidden from the enrollment to the nal follow-up visit.

Sample Collection
Subjects were admitted to the Phase Clinical Research Center of the hospital one day prior to each period. After an overnight fast (≥10 hours), the baseline blood samples were collected within one hour before study drugs dosing. Collection of postdose blood samples were within two minutes of the speci ed times. Five hours after administration of study drug, the time deviation could be extended to three minutes. Venous blood samples of upper extremities were collected into labeled ethylene diamine tetraacetic acid (EDTA) tubes for pharmacokinetic analyses before administration and at 0. 25 Within 1 hour after collection, blood samples of 4 mL were centrifuged at 3000 rpm for 10 minutes at 4 °C to separate plasma in a precooled centrifuge. Each plasma sample was divided into two aliquots, then transferred to corresponding labeled tubes, and one of which was in reserve. The plasma samples were transferred to -60 °C within 1 hour after centrifugation. After packaging with dry ice by professional cold chain logistics company (Shengsheng Supply Chain Management s.a, Shanghai, China), the plasma samples were transferred to the analytical facility (MicroConstants., Inc, Beijing, China) for assay, and temperature monitoring and adequate dry ice were supplied during transportation.

Analytical Method and Validation
Cipro oxacin plasma concentration was determined by a means of liquid chromatography-tandem mass spectrometry method. A XSelect HSS T3, 5.0 µm, 100 x 2.1 (Waters corporation. Milford, Massachusetts, U.S.A) mm column was used for separation at a ow-rate of 0.5 mL/min with column temperature of 30°C. The mobile phase consisted of water with 20 mM ammonium formate (Acros Organics, Belgium) and 0. ng/mL, and the LLOQ of quality control (QC) was also 1.87 ng/mL. The inspection contents of analytical methodology validation included between-run precision and accuracy, within-run precision and accuracy, recovery rate, selectivity (speci city), matrix effects, dilution reliability, stepwise dilution reliability, residual effect of HPLC injection, analytical batch length, reproducibility for reinjection of 72 hours, placement stability of processed samples, freeze-thaw stability, stability of samples, matrix effects, hemolysis effects, recovery rate, accuracy and precision, reproducibility for reinjection of 72 hours.

Follow-up
After the end of the two period of sampling, the subjects underwent a series of safety assessments before hospital discharge, which included physical examination, vital signs, 12-lead ECG, chest radiography, laboratory analysis of blood routine, urine routine and blood biochemistry, serum pregnancy test. The subjects would be permitted to leave the Phase Clinical Research Center of the hospital, if their assessments were satisfactory.
The subjects were followed up 3-7 days after hospital discharge, and inquired whether there were any subsequent AEs, occurrence of which would be recorded, the follow-up would be continued until the disappearance of the AEs. If the subjects experienced AEs during the study, they would be followed up until the AEs stabilized, disappeared, or lost to follow-up.

Safety Assessments
Safety Set (SS) consisted of all subjects who had received the study drug at least once after enrollment and undergone safety assessments, the role of SS was to evaluate the safety of the study drug. The incidence, time, severity, and relationship to the study drug of AEs were recorded by nursing and observations of the medical staff, and results of laboratory and pathology throughout the study. Clinical parameters for the safety assessments were obtained from physical examination, vital signs, 12-lead ECG, and laboratory analysis of blood routine, urine routine and blood biochemistry. The researchers calculated the amount and frequency of abnormal clinical parameters in the study, then detailly listed the abnormal clinical parameters and corresponding clinical explanations, and concretely described the changes in vital signs.

Pharmacokinetic and Statistical Analyses
Chromatogram collection and chromatographic peak integral of cipro oxacin and IS was performed by MassLynx v.4.1 (Waters, Milford, Massachusetts, U.S.A). Linear tting of the peak area ratio of cipro oxacin to IS and the concentration of the reference substance of cipro oxacin was to obtain a standard curve equation (weight = 1/x 2 ). The peak areas and concentrations obtained from MassLynx v.4.1 were imported into the Microsoft O ce Excel (Microsoft Corporation, Washington, U.S.A) to be used to calculate the mean, deviation, standard deviation, and variable coe cient (CV). The data were stored on a computer hard drive interfaced to the mass spectrometer for subsequent pharmacokinetic analyses.
Phoenix WinNonlin version 6.4 (Pharsight Corporation, Mountain View, California) were used for calculation of pharmacokinetic parameters, which included C max , AUC 0-t , AUC 0-∞ , T max , t 1/2 , and λz. AUC 0-t = the area under the plasma concentration-time curve from time 0 to time t, it was calculated by linear trapezoidal method, where time t was the last timepoint to collect blood sample AUC 0-∞ = the area under the plasma concentration-time curve from time 0 to in nity, it was calculated as AUC 0-t + C t /λz, where C t was the last measurable drug concentration, and λz was apparent elimination rate constant derived from linear regression analysis of ln(concentration-time) curve during the elimination phase T max = the time to maximum concentration (C max ), both T max and C max were actual measured values t 1/2 = ln2/λz, terminal elimination half-life

Bioequivalence Analyses
Bioequivalence of the two cipro oxacin hydrochloride tablets was determined by analysis of variance (ANOVA) after ln-transformation of the C max , AUC 0-t , and AUC 0-∞ , which was performed using Statistical Analysis Software (SAS) version (SAS Institute Inc., USA) 9.4 with a non-compartment model. A test product was considered bioequivalent to a reference product if 90% CIs of the test/reference GMRs for lntransformed pharmacokinetic parameters (C max , AUC 0-t , and AUC 0-∞) were within the acceptance range of 80.00% -125.00%.

Demographic Date
In the fasting study, twenty-four subjects were enrolled between the age of 18-43 years (mean ± SD: 27.9 ± 6.4 years), and consisted of 16 male subjects and 8 female subjects. The mean ± SD (range) height, weight and BMI of these subjects were 167.15 ± 8.46 cm (152.0-183.1 cm), 59.88 ± 8.39 kg (47.0-74.6 kg) and 21.34 ± 1.61 kg/m 2 (19.1-24.2 kg/m 2 ), respectively. Two subjects smoked occasionally, the other subjects never smoke, and none of the subjects had drinking history. Twenty-two subjects completed the study while two subjects withdrew at the end of rst period of the fasting study for personal reasons.
For the fed study, twenty-three subjects completed the whole study, and one subject were excluded, due to the use of penicillin eye drops two days before administration in the rst period. The twenty-three subjects consisted of sixteen male subjects and seven female subjects, the mean ± SD (range) age, height, weight and BMI of them were 27.8 ± 6.3 years (20-

Pharmacokinetics
The mean cipro oxacin plasma concentration-time curves after 250-mg single-dose oral administration of two cipro oxacin hydrochloride tablets in the fasting and fed studies were shown in Fig. 1 (datasets: Table S1). Comparisons of the pharmacokinetic parameters between the two formulations under the fasting and fed conditions were shown in Table 1 and Table 2

Bioequivalence
Bioequivalence assessments between the test and reference products using a con dence interval method after a single oral dose of 250 mg of cipro oxacin in healthy Chinese subjects in the fasting and fed studies were shown in Table 3 and Table 4, respectively.
The effects of administration sequence, period, and formulation on ANOVA of ln-transformed data for C max , AUC 0 − t , and AUC 0−∞ were shown in Table S2. In general, the xed factors (sequence of administration, period, and formulation) had no signi cant effects on the ANOVA of ln-transformed data for C max , AUC 0 − t and AUC 0−∞ .
The results of ANOVA for effects of the xed factors including administration sequence, period and formulation on ln-transformed data for the pharmacokinetic parameters (C max , AUC 0 − t , and AUC 0−∞ ) were shown in Table S3. No sequence of administration, period and formulation effects were found on ANOVA of ln-transformed data for the pharmacokinetic parameters.

Safety
In the fasting study, a total of 8 adverse events (AEs) occurred in 6 subjects (Table S4). 5 AEs were reported in 4 of 24 (16.7%) subjects who received a single-dose of the test product, included dermatitis (1/24), hyperuricemia (1/24), elevated heart rate (1/24), elevation of blood pressure (1/24), increased bilirubin (1/24), these AEs were all mild in severity, the outcome of 1 of 5 AEs was loss to follow-up, another one was remission, and the others were recovery. 2 of 24 (8.3%) subjects reported 3 AEs after administration of the reference products, which included dizziness (1/24), strain of lumbar muscles (1/24) and right patella osteomalacia (1/24), the severity of these AEs was mild, and the outcomes were all recovery. Not any subjects withdrew from the fasting study due to the AE. No serious AEs were reported throughout the fasting study.
Only 2 of 23 (8.7%) subjects experienced 2 AEs under the fed condition (Table S4), 1 of 23 subjects who received a single-dose oral administration of the test product reported one AE, which was hypotension accompanying with needlesickness, and severity of it was mild, the outcome was recovery. The other subject experienced AE due to the administration of the reference product, and the AE was also hypotension accompanying with needlesickness, which was mild and transient.

Discussion
We performed a clinical study to obtain some important information including pharmacokinetic properties of the test and reference products under the fasting or fed conditions, and within-subject CVs for C max , AUC 0 − t and AUC 0−∞ , the data for pharmacokinetic properties contributed to judge the accuracy of our study results and determine the bioequivalence between the test and reference products preliminarily, the data for within-subject CVs could be used for estimating the sample size and improving the study scheme in subsequent large-scale study if necessary, and if a test product was not equivalent to the reference product, we tried to change the particle size or formulation technology of the test product.
In accordance with the published studies, after a single dose oral administration of cipro oxacin of 500 mg in healthy volunteers, within-subject CVs for C max , AUC 0 − t and AUC 0−∞ after were in the approximate range of 12.8-19.6%, 11.0-22.0% and 9.95-26.5%, respectively [17][18][19][20]. The sample sizes range of 20 to 26 was adequate to ensure a power of 90% to correctly evaluate bioequivalence under the following assumptions: α = 0.05, 0.95 < AUC 0 − t /AUC 0−∞ < 1.05, with within-subject CV of 20.0%, and the bioequivalence criterion was that 90% CIs of the test/reference GMRs for ln-transformed C max , AUC 0 − t , and AUC 0−∞ were completely included in the de ned interval (0.80, 1.25) [21][22]. We chose a number of 24 subjects in our study, considering the following factors: the number of subjects was generally 24 in the previous published studies [17][18][19]23]; probable withdrawal of subjects from the study; the withinsubject CVs data mainly derived from male subjects [17][18]20], the introduction of female subjects might increase the values for the CVs. For our study, the powers of test calculated for C max under the fasting and fed conditions were 87.3% and 90.3%, respectively, which were both close to 90%, and the powers of test calculated for AUC 0 − t and AUC 0−∞ were all > 99.9%, therefore our choice of the sample size for subjects was appropriate.
Our study mainly aimed to evaluate the bioequivalence of the test and reference products after a single oral dose of 250 mg of cipro oxacin hydrochloride in healthy Chinese subjects under the fasting and fed conditions. A total of 48 eligible subjects were enrolled in our study, consisted of 24 subjects in the fasting study and 24 subjects in the fed study. 23 of 24 subjects completed the clinical trial in the fed study, because one subject withdrew from the study before administration in the rst period, due to personal negligence. In the fasting study, two subjects withdrew at the end of rst period for personal reasons, the data of the them obtained from the rst period of the fasting study were included in the pharmacokinetic analyses, but not safety and bioequivalence assessments.
Cipro oxacin exhibited high safety properties with no drug-related severe AEs found through the study. A total of 8 of 47 subjects reported AEs in our study including the fasting and fed studies, all AEs were mild in severity, and outcomes of most AEs were cure or remission without additional medical assistance, most of the AEs were determined as "probable not" to be related to our study drugs.
As shown in Table 3 and Table 4, the results from our study suggest that the test product was bioequivalent to the reference product under the fasting and fed condition in accordance with the de ned criteria for bioequivalence, all of the 90% CIs for the GMRs of ln-transformed values for C max , AUC 0 − t and AUC 0−∞ fell within the acceptance range of 80-125%.
There were plenty of pharmacokinetics studies about cipro oxacin after a single dose oral administration of a cipro oxacin tablet in adult patients or healthy subjects, but most of studies on the pharmacokinetics of cipro oxacin mainly focused on the dose of 500 mg, the studies about a single dose of 250 mg were rare among them [14,[24][25][26][27][28][29][30][31][32][33]. Several previous studies indicated that the 250-mg singledose of cipro oxacin was e cacious and safe in the therapy of uncomplicated gonorrhea,equally to the 500-mg dose of cipro oxacin [7,[34][35][36][37], so it's meaningful to investigate the pharmacokinetics of a single dose of cipro oxacin 250 mg. The cipro oxacin pharmacokinetic parameters determined after a single-dose oral administration of cipro oxacin hydrochloride of 250 mg in our study were somewhat different from those reported in published study [14], maybe due to racial difference [38]. The median (range) of T max after administration of the test and reference products under the fasting condition were 0.75 (0.5, 2) and 1.00 (0.5, 2) hour, respectively; for the fed condition, the corresponding values were 1.25 (0.75, 3) and 1.25 (0.5, 3) hour, demonstrating that cipro oxacin was rapidly absorbed under both the fasting and fed condition, and food could delay the absorption of cipro oxacin, the preliminary conclusion about the "food effect" was consistent with a published study [39], of course, the conclusion need further investigation and con rmation. The subjects of our study were all healthy adults; therefore, the ndings were not necessarily applicable to patients or other populations.

Conclusions
In the study, the generic (test) and innovator (reference) product of cipro oxacin hydrochloride of 250 mg were bioequivalent after a single oral dose administration under the fasting and fed conditions. Both two formulations were well tolerated.

Declarations
Ethics approval and consent to participate The study was approved by independent Ethics Committee of the Guangdong Province Traditional Chinese Medical Hospital (registration number: A2017-002-1-02). Informed consent was obtained from all individual participants included in this study.

Consent for publication
Not applicable Availability of data and materials All data generated or analysed during this study are included in this published article and its supplementary information les.
Abbreviations: PK, Pharmacokinetic; SD, standard deviation; C max , maximum concentration; AUC 0-t , area under the plasma concentration-time curve from time 0 to time t; AUC 0-∞ , area under the plasma concentration-time curve from time 0 to in nity; λz, apparent elimination rate constant derived from linear regression analysis of ln(concentration-time) curve during the elimination phase; t 1/2 , terminal elimination half-life. Abbreviations: PK, Pharmacokinetic; GMR, geometric mean ratio (Test/Reference); CI, con dence interval; CV, coe cient of variation (within intra-subject); C max , maximum concentration; AUC 0-t , area under the plasma concentration-time curve from time 0 to time t; AUC 0-∞ , area under the plasma concentrationtime curve from time 0 to in nity. Abbreviations: PK, Pharmacokinetic; GMR, geometric mean ratio (Test/Reference); CI, con dence interval; CV, coe cient of variation (within intra-subject); C max , maximum concentration; AUC 0-t , area under the plasma concentration-time curve from time 0 to time t; AUC 0-∞ , area under the plasma concentrationtime curve from time 0 to in nity.