INTRODUCTION:

Cefuroxime axetil (CA) is a second-generation broad-spectrum cephalosporin antibacterial drug. It is resistant to beta-lactamase and proved to be relatively safe. Cefuroxime axetil is indicated for systemic use to treat various infections in adults and children starting from the age of 3 months.

The recommended course therapy is seven days ranging from 5-10 days according to the patient's need with doses from 250 to 500mg twice daily. In Lyme disease, CA may be given in 500mg dose twice daily for 14 days with a range of 10-21 days^1,2. A very recent study conducted in Denmark indicated that cefuroxime given intravenously in 750mg twice daily was effective against S. pneumoniae. A higher dose of 1500mg 3 times daily was considered the optimal dosing schedule against E. coli ³. Cefuroxime axetil is available as 125, 250 and 500 mg tablets and as a suspension containing 125mg CA per 5ml. The drug is also available in vials for injection containing 750mg/15ml, 1.5gm/50ml, and 7.5gm/100 vials^1,2. Developments in the formulation of drugs in different dosage forms and routes of administrations applying various pharmaceutical technologies are ongoing for improving and optimizing the drug performance^4-9.

Orally administered CA, inactive ester pro-drug, is absorbed from the GIT and rapidly hydrolyzed in the intestinal mucosa and blood by esterase enzymes to release the active antibiotic cefuroxime into the circulation. Limited information is available concerning the effect of food on the rate and extent of CA absorption from GIT. Previous researches conducted before about 30 years ago indicated that optimum absorption of CA occurred when it was given shortly after food intake^10,11. Interestingly, a very recent investigation in china¹² demonstrated that administering CA after food caused a significant increment in the extent of CA absorption from GIT, and consequently its extent of bioavailability (BA) in comparison to the fasting state. Thus, it was recommended to administer the drug after food¹². The maximum plasma concentration (C_max) of cefuroxime was attained approximately 2-3 hours after taking the medication with food^10-12.

The plasma protein binding degree of cefuroxime ranged from 33-50%, depending on the methodology. The apparent volume of distribution (Vd) after oral intake was 50 liters with %CV of about 28%. Cefuroxime is not metabolized in the liver, and the kidneys mainly excrete it. Thus, in patients with a remarkable reduction in renal function, it is recommended that the drug dose be decreased. The renal clearance of the drug occurs via glomerular filtration and tubular secretion, and it was found to be between 125-148ml/min/1.73m². The presence of hepatic dysfunction may have no impact on the cefuroxime PK since the kidneys are the major route of the drug elimination from the body. The terminal plasma elimination half-life (T_half) of cefuroxime ranged from 1-1.5 hours^1,2.

Clinical observations documented in the last three decades by pharmacists, health professionals and registration authorities found that two identical dosage forms containing the same dose of the same drug may exhibit remarkable variabilities between their therapeutic and/or their adverse effects, which were in most instances due to significant differences in their rate and/or extent of drug absorption and consequently in their rate and/or extent of drug BA. These interesting findings justify the therapeutic failure and/or the appearance of adverse effects if the patient uses a non-bioequivalent generic drug product rather than the brand drug product. Accordingly, BE documentation between generic and brand drug products became obligatory documents required by national and international health agencies such as the FDA and EMEA to register and market generic drug products to assure a safe and effective remedy to the patients^13-19. Keeping drug levels within the therapeutic ranges is a vital issue in drug therapy to achieve the optimal effect with minimal adverse effects. Therefore, PK, BA and BE studies are carried out continuously in many countries and for various types of drugs to study and evaluate the PK profiles of the medicines in their populations. Among these studies were conducted for medications such as azithromycin²⁰, cefixime²¹, fluconazole^22,23, betahistine²⁴, doxazocin²⁵, cyclosporine²⁶, amlodipine, valsartan, and hydrochlorothiazide²⁷.

Arabic pharmaceutical factories manufacture so many generic pharmaceutical products with prices much lower than the corresponding multinational competitors. Regarding antibacterial drugs, particularly cefuroxime, achieving the necessary therapeutic plasma concertation that produces a maximum effect with a minimum adverse consequence is a special concern for successful therapy. If the administered dose yields plasma concentration below the minimum therapeutic efficacious level that assures complete eradication of the microorganism which causes the infection, then the potential risk for developing resistance to the drug may be raised. On the other extreme, if the given dose produces plasma levels above the maximum therapeutic levels, then drug therapy may be accompanied by adverse effect (s), which lead to either stop using the drug, and replaced it with other alternative medicines and/or using a combination of antibacterial medications which in turn have many disadvantages to the patient in term of the health and the cost. Therefore, many BE studies were executed for CA in different countries to establish the BE of their generic drug products before registration and marketing. Among these studies were performed in Taiwan²⁸, Arabic countries^29-31, Greece³², Poland³³, Pakistan³⁴, Thailand³⁵, Korea³⁶, and Brazil³⁷.

The purpose of this investigation was to compare the PK profiles and to evaluate the BE between a newly formulated generic CA 500mg tablets against the same dose of the brand product Zinnat tablets manufactured by Glaxo Smith Kline, UK, after administering both drug formulations to Arabic healthy male adult fasting subjects.

MATERIALS AND METHODS:

Invitro dissolution study:

According to the recommendation presented in FDA guidance on dissolution^38,39, a promising invitro dissolution performance is a prerequisite for BE evaluation between a newly developed test/generic drug formula against the reference/brand drug formula. Besides, the dissolution study should be achieved under discriminating dissolution conditions that involve an appropriate choice of dissolution apparatus, the speed of rotation, the volume and PH of the dissolution media. The most suitable and useful way to compare the dissolution profiles between two or more drug formulations is by calculating the similarity factor (F2). The dissolution profiles of two drug formulas (for example, generic versus brand) can be considered similar if an F2 value of more than 50(50-100) is obtained, which confirm the pharmaceutical similarity between both drug formulas, and may indicate sameness or equivalence of the invivo performance of both products^38,39.

The samples (n=12) of the newly formulated generic CA 500mg tablets against the brand tablets were compared under the following dissolution conditions: dissolution apparatus-II paddle method was used with speed 50rpm, 900ml phosphate buffer at PH 1.2, 4.5, and 6.8, and the temperature was set at 37±0.5 ^◦C. Samples of aliquot were taken from the dissolution media after 15, 30, and 45minutes, and the volume of the sample taken was replaced by the same volume of the dissolution media. The concentrations of the drug were measured by an analytical method described previously⁴⁰.

Study design:

This study was a fasting, open-labeled, laboratory-blind, single-dose, 2-treatment, 2-period, 2-sequence, randomized, 2-way crossover design, with six days wash-out interval between periods. Such design involves using an equal number of randomly assigned subjects to each dosing sequence of the treatments (test versus reference). If drop out and/or withdrawal occur during the study, this will lead to an unbalanced design. Therefore, in the first period of the study, half of the participants were given a single dose of the test drug product, which was a newly formulated generic CA 500 mg tablets, and the other half of the participants were given the same dose of the brand reference drug product Zinnat tablets produced by GlaxoSmithKline, UK according to a randomization table established in the study protocol. After a wash-out interval of six days (in period 2), the order of the drug products administration was reversed. Such design is widely applied globally, and the most recommended one according to the international guidance on BA and BE^13-19,41.

Study protocol:

A study protocol including the informed consent form was prepared by the principal investigator/study director following ICH guidelines for good clinical practice^42,43 and the declaration of Helsinki⁴⁴. The clinical investigator, the institutional review board (IRB) and the principal investigator reviewed and approved the study protocol before study conduct. All study details were described in the protocol involving the clinical and bioanalytical procedures, PK and statistical analysis, and eventually BE decision. Any necessary amendments required to be made in the study protocol by the principal investigator/study director could not be achieved unless additional written approvals from the clinical investigator and IRB were obtained, except in urgent cases in which there is a need to overcome immediate hazard to the participants and/or when the amendments are so minor such as logistical or administrative alterations.

Participants:

Based on previous BE studies conducted in different populations for CA^28-37, it seemed that participation of 24 subjects was found to be enough to obtain adequate power for the conclusion of BE between the test and the reference CA formulations. Therefore, 35 subjects were screened to account for any dropout and/or withdrawal during the study, which is very common in most clinical trials^13-19,41. The participants signed the consent forms at the screening phase before study commencement.

Arabic adult male Caucasian subjects with normal physical condition, ages between 18-48 years, body mass index (BMI) range from 18-30kg/m² and who are willing to follow the requirements of the study protocol found in the informed consent were chosen to be screened for clinical examinations. The inclusion criteria were: 1) non-smokers or light smokers (> 10 cigarettes per day), 2) no illicit drug or alcohol abuse, 3) no history of contraindication and/or hypersensitivity to CA and any related material, 4) normal clinical examinations including vital signs, ECG, hepatic, renal, respiratory, cardiac, gastrointestinal and mental, 5) normal clinical laboratory examinations including biochemistry, hematology, routine urine analysis, negative for HIV and hepatitis B and C), 6) no medications were taken by the participant other than paracetamol for the last two weeks prior the study, 7) no blood donation, hospitalization or participation in any clinical trials such as PK, BA or BE before two months of screening.

Drug administration and blood sampling:

On the first day of each study period, the participants were admitted to the clinical venue before about 16 hours before drug administration (4p.m.) to achieve alcohol and drug abuse examinations, in addition to the vital signs including blood pressure, pulse and temperature. The eligible participants were received an identity number according to the randomization table as per the study protocol. The participants served a standard dinner at 12 hours pre-dosing (8 p.m.) and stayed confined in the clinical venue until 8 hours post-dosing, which is the last blood sample withdrawal at the end of each period, and discharge of the participants.

On the morning of the second day of each study period (8 a.m.) and after overnight fasting of 12 hours, an intravenous cannula was inserted into a right forearm antecubital vein of each participant. The cannula was left until the end of the last blood sample withdrawal. Five ml blood sample was obtained from each participant before drug products administration (test and reference) which is considered as (0-hr) sample, and then at 0.33, 0.67, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, and finally at 8.0 hours post-dosing. The drug products were given with 240ml of tepid water, followed by a mouth check to assure drug product intake by the participant. The cannula was immediately washed after each blood sample withdrawal with 0.5ml of normal saline containing 20 units of heparin/ml. Moreover, two drops of blood were discarded before the next blood sample withdrawal to eliminate residual blood in the cannula. To separate the plasma, each blood sample was directly transferred to tubes containing heparin and then immediately centrifuged for 5 minutes at 4000rpm. The separated plasma was directly stored in a deep freezer at −30±5^◦C until the day for analyzing cefuroxime concentrations in plasma samples.

The participants refrained from food intake until 4 hours post-dosing and from water for 2 hours pre- and 2 hours post-dosing. Standard lunches were served to the participants 4 hours after dosing. The meals were identical in both study periods, and the participants were asked to take the whole meal. Xanthine-containing products were not allowed 12 hours pre-dosing and until the end of each study period. Grapefruit juice or beverages abstained before one week of drug administration until the completion of the study. Besides, the participants were banned from sleeping or lying during the first 4 hours of drug intake. The subjects were left ambulatory and free for sitting or standing but without any strenuous activity.

Safety and tolerability evaluation:

The participant’s safety and tolerability for cefuroxime were followed by performing clinical laboratory examinations including hematology, biochemistry and urinalysis directly at the end of the first period, before conducting the second period, and then at the end of the second period before the participant’s discharge from the study. The clinical examinations included recording the vital signs (blood pressure, pulse and temperature) at about 1.0 hour before drug products intake for each period, and then at 1, 2, 3, 4, 6, and lastly at 8 hours post-dosing.

Cefuroxime determination in plasma:

Previously described HPLC method was used for determining the concentrations of cefuroxime in plasma⁴⁵. The linearity of the method was established over concentrations range from 0.01-50μg per ml plasma with a correlation coefficient equaled to 0.999. The relative standard deviation values for the precision studies were below 1%, and for the accuracy, evaluations were more than 98 percent⁴⁵. All the analytical validation results were within the limits allowed by FDA guidelines on bioanalytical method validation^46,47. Each analytical run/batch contained the standard calibration curve, quality control (QC) samples (low, mid and high), and all the unknown authentic plasma samples containing cefuroxime obtained from both drug product^46,47.

Pharmacokinetic and statistical analysis:

Calculation of the PK parameters C_max, AUC_0–t, AUC_0–∞,T_max, K_elimination (l_z), T_half MRT, Cl, and Vd, in addition to statistical analysis of the above parameters for BE evaluation, were executed by Kinetica software. The above parameters were determined by standard methods applying non-compartmental data analysis^48,49. The statistical tests done were^50,51: 1) ANOVA were applied to compare the plasma concentrations of cefuroxime at each sampling time point (13 data points) obtained from the test product against the corresponding concentrations obtained from the reference product at the same time point, 2) ANOVA was carried out for all the above parameters to account for the possible sources of variations including period, subject, and formulation. 3) ANOVA, 90% confidence interval (90% CI), and Schuirmann’s two one-sided t-tests⁵² were accomplished solely for the ln-transformed parameters used for BE evaluation, namely C_max, AUC_0-t and AUC_0-∞, as recommended by international guidance on bioequivalence such as FDA and EMEA^13-19,41, besides 4) non-parametric Friedman design and Kruskal-Wallis test⁵³ were conducted to assess the statistical difference if any between the T_max and MRT of the test against the reference formulas.

The average bioequivalence between two drug formulas (test versus reference) was concluded if 90% CI interval for ln- C_max, AUC_0-t and AUC_0-∞ range between 80.00-125.00^13-19,41. The variability between the PK parameters obtained from two drug formulations is regarded statistically not significant at a 5% significance level (µ =0.05) if P ³ 0.05^50,51. Microsoft Excel was employed for plotting the plasma concentration versus time data of cefuroxime and for introducing the descriptive statistics including arithmetic mean, geometric mean, a ratio of means, maximum values, minimum values, median, standard deviation (SD), coefficient of variation (CV), and relative BA of all the calculated PK parameters.

Definition of the measured PK parameters are as follow^48,49: C_max= the maximum concentration of cefuroxime in plasma, and the time to attain C_max (T_max) were taken directly from the observed experimental concentration-time profile of each participant, K_elimination or λ_z= the terminal elimination rate constant was obtained by linear regression of not less than three points at the terminal phase of log-concentrations of cefuroxime versus time profile, T_half= the terminal elimination half-life equaled to 0.693/λ_z, AUC_0-t= the area under concentration versus time curve was computed by Trapezoidal rule from time zero up to the time of last blood sample taken (t_last), AUC_t-∞= the extrapolated area (AUC_extrapolated) is the area under plasma concentration-time curve from t_last to infinity was computed as C_last/λ_z where C_last is the last measurable cefuroxime concentration which equal to or above the LLOQ of the drug (0.01 μg per ml plasma), AUC_0-∞= the area under plasma concentration-time curve from time zero to infinity was the sum of AUC_0-t+AUC_t-∞, %AUC_extrapolated= (AUC_t-∞/AUC_0-∞)×100, MRT = the mean residence time of the drug in the body = AUMC/AUC where AUMC represent the area under moment curve which was computed from the AUC multiplied by the time (t) at each concentration-time point of the AUC, Cl/F = total body clearance of cefuroxime for each subject calculated by dividing the dose given (500mg CA) divided by the AUC_0-∞ of the subject and F is the absolute BA of the drug, Vd/F = apparent volume of distribution of the drug for each subject equal to the Cl of each subject divided by his λ_z^48,49.

RESULTS AND DISCUSSION:

Dissolution profiles:

The F2 value calculated in the present study approached 100 due to the superimposed dissolution profiles of the test and the reference formulas tested in phosphate buffer at a different PH of 1.2, 4.5, and 6.8, which indicated sameness and pharmaceutical equivalence of both formulas, and thus, this invitro dissolution result was encouraging for proceeding to invivo BE study as recommended by FDA guidance on dissolution^38,39.

Study design:

Thirty-five individuals were screened in this study, four individuals were found to be not eligible due to demographic and clinical reasons, one individual withdrew the evening before period 1 and other individual withdrew at the morning of period 1 before drug products administration for personal reasons, in addition to that, one more individual was not allowed to participate by the clinical investigator before drug products administration of period 1 because of abnormal vital signs. Hence, ultimately twenty-eight individuals were given both drug products and completed both periods of the study.

Safety and tolerability:

Clinical examinations, including vital signs and clinical laboratory tests involving hematology, biochemistry and urinalysis, were done to each participant immediately at the end of period 1, before period 2, and then at the end period 2 before the participant’s discharge from the study. All participants tolerated both CA formulas well, and they completed the study without any noticeable changes in their clinical baseline properties, such as vital signs and clinical laboratory examinations. No signs of AEs, ADRs, and SAEs were recorded during the entire project. The primary demographic and clinical properties of the participants are listed in Table 1.

Table 1. Properties of 28 Arabic adults healthy male completed the study

Properties	Mean±SD	(%CV)	Range
Age (years)	26.4±7.2	27	18-45
Height (m)	1.74±0.06	3.3	1.65-1.93
Body weight (kg)	73±7.0	10	60-85
BMI (kg/m²)	23.9±2.1	8.8	18.9-28.7
Systolic blood pressure (mmHg)	116.1±9.2	7.9	110-130
Diastolic blood pressure (mmHg)	70.4±1.9	2.7	70-80
Pulse (beat per minute)	76.9±2.2	2.9	73-82
Temperature (°C)	36.6±0.13	0.36	36.4-36.8

Cefuroxime plasma concentrations:

Cefuroxime plasma concentrations were measured by a sensitive, specific, accurate and precise method⁴⁵ following FDA bioanalytical method validation guidelines^46,47. The sensitivity of the method which covered cefuroxime levels from 0.01-50 μg/ml plasma was successfully applied for reliable description of the concentrations versus time profiles and the PK behaviors obtained from both formulas, including the absorption, distribution and terminal elimination phases of the drug as illustrated in Figures 1A and 1B. Six days wash-out interval between periods was very enough to ensure the absence of carryover effects from period 1.

Cefuroxime plasma levels above the LLOQ of 0.01 μg/ml were observed in the first samples taken at 0.33 hour post-dosing for all participants and for both drug formulas indicating rapid and similar absorption rates of cefuroxime for both drug formulations. Similarly, plasma levels of cefuroxime were detected in the last samples harvested at 8 hours post-dosing for all participants and for both cefuroxime formulas reflecting the close similarity in elimination rate of the drug for both formulations, as depicted in Figures 1A and 1B. The drug reached its maximum levels in plasma for both products after about 2 hours (mean 1.8, range 0.7-3 hours). After that, the cefuroxime declined monoexponentially, as illustrated in Figures 1A and 1B and presented in Table 2.

Visual inspection of Figures 1A and 1B clearly indicates that cefuroxime plasma concentration-time profiles of both formulas are very identical and overlapping. Statistical comparison applying ANOVA tests between the plasma concentrations of cefuroxime at each time point (13 data points from 0.33-8 hours post-dosing) for the test formula against the corresponding concentrations at the same time point for the reference formula exhibited no significant differences (P > 0.05). Thus, the results mentioned above clearly manifest the close similarity in the invivo performance of the test and the reference cefuroxime formulas, including absorption, distribution and elimination processes. The present findings agree with previously published BE studies for CA tablets conducted in different populations^28-36.

Figure 1. Plasma concentrations-time profiles (Mean±SD) of cefuroxime following administration of 500 mg cefuroxime axetil tablets of the test and reference products. (A) linear scale and (B) semilog scale

Cefuroxime pharmacokinetics:

The descriptive statistics of cefuroxime’s PK parameters computed from the concentration-time profile of each participant after administering the test and the reference drug formulas are summarized in Table 2. It is very clear from visual inspection of Table 2 that the descriptive statistics (the mean, the ranges and %CV) of all PK parameters of both formulas were very comparable and demonstrated low inter-individual differences, except T_max, which showed a relatively higher %CV with a mean value of 40% which is usual for most drugs (Table 2). Therefore, it is evident from this research that both CA formulations demonstrated similar PK behaviors in the body in terms of the rate and extent of drug absorption and total drug exposure. All the PK parameters presented in Table 2 are identical to those introduced in other studies after administering CA 500 mg tablets to different populations^28-36, which indicates that ethnicity may have no superior effectiveness on CA pharmacokinetics.

For both CA formulations, the % extrapolated AUC was extremely small and had a negligible contribution to the total AUC (AUC_0–∞) as appear in Table 2, which indicate that blood sampling for 8 hours post-dosing and using LLOQ of cefuroxime equal to 0.01 μg/ml plasma were quite enough for reliable computation of all cefuroxime’s PK parameters. Since the differences in the rate and/or extent of drugs absorption are the main reasons for the absence of BE between two drug formulations^{13-19, 48-51}, MRT, which is the drug’s mean residence time of the drug in the body, was also measured in this research. The MRT is the sum of the mean absorption time plus the true mean residence time of the drug was found to be similar for both CA formulas (Table 2), and due to the close similarity in the T_half obtained after the administration of both CA formulations (Table 2). Thus, it can be concluded that the rate of cefuroxime absorption from both formulations is, to a good extent, identical. Consequently, the close resemblance in the rate and extent of cefuroxime absorption (C_max, T_max, MRT and AUC) from the test and reference formulas (Table 2) suggest the presence of BE between both formulas.

Table 2. Pharmacokinetic parameters of cefuroxime after administering 500mg cefuroxime axetil tablets of the test and the reference products Test product

Parameters	Mean	±SD	%CV	Min	Max	Geomean
C_max(μg/ml)	4.61	1.17	25	2.83	6.98	4.48
T_max(hr)	1.17 (1.50)*	0.63	38	1.0	3.0	**
AUC_0-t(μg.hr/ml)	13.96	3.46	25	9.41	21.60	13.56
AUC_0–∞(μg.hr/ml)	14.28	3.65	26	9.48	22.7	13.87
%AUC_extrapolated	0.32	0.29	**	0.06	1.15	**
λ_z(hr^-1)	0.606	0.085	14	0.422	0.718	**
T_0.5(hr)	1.17	0.19	16	0.97	1.64	**
MRT (hr)	2.78	0.49	18	2.11	3.85	**
Cl/F (l/hr)	30.3	7.6	25	18.3	43.8	**
Vd/F (l)	50.0	10.6	21	33.8	73.1	**

Reference product

Parameters	Mean	±SD	%CV	Min	Max	Geomean
C_max(ng/ml)	4.77	1.29	27	2.35	8.14	4.61
T_max(hr)	1.77 (1.6)*	0.70	40	0.67	3.0	**
AUC_0-t(ng.hr/ml)	14.25	3.18	22	8.58	21.11	13.91
AUC_0–∞(ng.hr/ml)	14.56	3.35	23	8.73	22.07	14.19
%AUC_extrapolated	0.30	0.25	**	0.06	1.02	**
λ_z(hr^-1)	0.611	0.081	13	0.444	0.769	**
T_0.5(hr)	1.16	0.173	15	0.90	1.56	**
MRT (hr)	2.78	0.45	16	2.10	3.65	**
Cl/F (l/hr)	30.0	7.1	24	18.8	47.6	**
Vd/F (l)	49.2	8.9	18	31.8	68.6	**

*Median, **The values of these parameters have no statistical significance

Statistical analysis and bioequivalence evaluation:

ANOVA tests elucidated no significant differences (P ³ 0.05) for cefuroxime’s PK parameters after administering the test formula against the corresponding parameters obtained after the administration of the reference formula, as shown in Table 3. Besides, no significant differences were also found for ln-transformed values of C_max, AUC_0-t and AUC_0–∞ (Table 3). Interestingly, the source of variation accompanied with BE studies, particularly the formulation (which is regarded as the main source of variation between the test and the reference drug formulas), the period, and the sequence factors, manifested no significant variation with P values much higher than 0.05 as shown in Table 3, which clearly indicate no significant differences between the drug formulas, and the study was properly designed and conducted. Furthermore, non-parametric Kruskal-Wallis and Friedman design tests demonstrated no statistical variations between the T_max and MRT values of the test against the reference CA formulas.

Table 3. ANOVA tests for the pharmacokinetic parameters of the test versus the reference products

Parameters	Source of variation and their P values*
Parameters	Period	Formulation	Sequence
C_max	0.3015	0.9812	0.2751
AUC_0-t	0.3677	0.9884	0.2980
AUC_0–∞	0.3370	0.9576	0.3066
Ln C_max	0.2751	0.9126	0.3837
Ln AUC_0-t	0.4440	0.8996	0.4588
Ln AUC_0–∞	0.4185	0.9244	0.4705
λ_z	0.2239	0.7111	0.9752
T_0.5	0.1409	0.6505	0.9608
MRT	0.6835	0.9474	0.4093

*No significant difference P ³ 0.05

The relative BA and the geometric mean ratio for the primary PK parameters recommended for BE evaluation (C_max, AUC_0–t and AUC_0–∞) of the test/reference CA formulas were almost equal to 100%, as displayed in Table 4. Notably, the ranges of 90% CI for ln-transformed values of C_max, AUC_0-t and AUC_0–∞ for the test/reference formulas (Table 4) were within the BE acceptance range of 80.00% to 125.00% according to international guidelines such as FDA and MEA^13-19. In addition to that, Schuirmann’s two one-sided t-tests supported the results obtained from 90% CI tests, as shown in Table 5.

Thus, based on all the results mentioned above obtained from this investigation, it can be concluded that the newly formulated generic CA 500mg tablet is bioequivalent to the reference brand product Zinnat tablet manufactured by GlaxoSmithKline, UK. Therefore, the generic formula may be considered interchangeable with the brand product in clinical practice and may be prescribed as a safe and effective alternative to Zinnat tablet.

Table 4. Geometric mean ratio, relative bioavailability and 90 % confidence interval (90% CI) for the test versus the reference products

Para meter	Geomean ratio	Relative bioavailability*	90% CI lower limit	90% CI upper limit
C_max	0.97	0.97	93.26	108.27
AUC_{0 – t}	0.98	0.97	94.73	104.77
AUC_{0 – ∞}	0.98	0.98	94.83	104.80

^a Relative bioavailability =arithmetic mean test/arithmetic mean reference.

Table 5: Schuirmann’s two one-sided t-test for pharmacokinetic parameters of the test versus the reference products

Parameter	Lower t(26df)	Upper t(26df)	Accepted T_L&T_U ³ t(0.05-26 df)
C_max	4.9924	5.2141	1.7056
AUC_{0 – t}	7.4242	7.6790	1.7056
AUC_{0 – ∞}	7.4752	7.6670	1.7056

CONCLUSION:

This study introduced the PK and the relative BA (bioequivalence) of a newly formulated generic CA 500 mg tablet compared to the reference brand product Zinnat tablet after administering both products to Arabic fasting healthy male adult subjects. Based on international guidance on bioequivalence like FDA and EMEA, no statistical differences were found between all the PK parameters of the generic and the brand CA tablets. Therefore, both products were bioequivalent and may be interchangeable in therapy with CA 500 tablets. Besides, the newly formulated generic CA 500 mg tablet may be a safe and effective alternative to the brand product Zinnat tablet in clinical practice. All participants tolerated both products well, and they were discharged from the study without any significant changes in their clinical baseline properties.

ACKNOWLEDGMENT:

The authors wish to acknowledge all the participants and the staff involved in this study—great thanks and appreciation to the medical student Miss Manar Al-Tamimi for her distinguished technical help.

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Received on 10.09.2021 Modified on 28.09.2021

Research J. Pharm. and Tech. 2022; 15(5):2184-2192.

DOI: 10.52711/0974-360X.2022.00363

Duaa Jaafar Jaber Al-Tamimi¹, Mustafa Ihssan Abbas Al-Mahroos²,

Mariam Jaafar Jaber Al-Tamimi³, Jaafar Jaber Ibraheem^3,*

RESULTS AND DISCUSSION:

Table 5: Schuirmann’s two one-sided t-test for pharmacokinetic parameters of the test versus the reference products

CONCLUSION:

Duaa Jaafar Jaber Al-Tamimi1, Mustafa Ihssan Abbas Al-Mahroos2,

Mariam Jaafar Jaber Al-Tamimi3, Jaafar Jaber Ibraheem3,*

RESULTS AND DISCUSSION:

Table 5: Schuirmann’s two one-sided t-test for pharmacokinetic parameters of the test versus the reference products

CONCLUSION:

Duaa Jaafar Jaber Al-Tamimi¹, Mustafa Ihssan Abbas Al-Mahroos²,

Mariam Jaafar Jaber Al-Tamimi³, Jaafar Jaber Ibraheem^3,*