Bioequivalence of two lamivudine tablet formulations

The present study describes the determination of the bioavailability of a new commercial tablet formulation of lamivudine (CAS 134678-17-4) compared with a reference formulation. The comparative bioequivalence of the test and a reference formulation (each 3 x 150 mg) was assessed in 24 healthy volunteers by means of a randomized two-way crossover design. Prior to the study both the test and reference formulations were examined for conformation to chromatographic purity and drug content. Each volunteer received the test (T) and the reference formulation (R) with a one-week drug-free interval between administrations. The plasma concentrations of T were monitored over a period of 12 h after drug administration using a sensitive HPLC method. Pharmacokinetic parameters for T were determined from plasma concentration-time data. Statistical tests were carried out at 90% confidence intervals using a parametric method (three-way ANOVA) for AUC and Cmax, and non-parametric method for Tmax. The present study showed that both formulations were bioequivalent for the geometric mean of AUC(0-12), AUC0-infinity), Cmax, and Tmax at the 90% confidence interval. The bioavailability of the test (%) was 96.7, 93.3, 99.7, 100.3, respectively. The T:R ratio was, in each case, well within the acceptable range of 100 +/- 20%.     

Bioequivalence evaluation of two rosiglitazone tablet formulations

A randomized, two-period, two-sequence, crossover study was conducted on 28 healthy male volunteers to compare the bioavailability of two rosiglita-zone (CAS 122320-73-4) tablet formulations, a test and a commercially available original preparation (reference), under fasting conditions. The two preparations were given in a dose of 8 mg with a 7-day washout period between the two preparations. Eighteen blood samples were collected over 24 h, plasma rosiglitazone concentrations were determined by locally validated high performance liquid chromatography (HPLC) assay, and pharmacokinetic parameters were analyzed by the standard non-compartmental method. The mean+/-SD of AUC0-->t, AUC0-->infinity, Cmax, Tmax, and t1/2 were 4.80+/-1.89 and 4.76 +/-1.94 microg x h/ml, 5.17+/-2.11 and 5.08 +/- 2.27 microg x h/ml, 0.93+/-0.24 and 0.99+/-0.34 microg/ml, 1.0 +/-0.4 and 0.8+/-0.5 h, and 5.0+/-2.0 and 5.0+/-2.0 h for the test and reference formulation, respectively. ANOVA did not show significant formulation, period, or sequence effect for any of the pharmacokinetic parameters. The 90 % confidence intervals of the mean differences between log-transformed values of the two formulations were 93.09 % to 109.73 %, 94.04 % to 111.70 %, and 89.70 % to 103.24 % for AUC0-->t, AUC-->infinity, and Cmax, respectively. It is concluded that the two formulations are equivalent in relation to the rate and extent of absorption.     

Bioequivalence study of two different tablet formulations of carvedilol in healthy volunteers

OBJECTIVE: The aim of this study was to compare the extent and rate of absorption of two different carvedilol (CAS 72956-09-3) tablet formulations: 25 mg tablets, as the test formulation and the reference innovator product (25 mg tablets). METHODS: This study was designed as a single-dose, open-label, randomised, with a two-period and two-sequence crossover design, with blind determination of drug plasma concentration and a minimum 7-day washout period. Twenty-four healthy volunteers of both sexes were randomly assigned to treatment sequences. Carvedilol concentrations were determined in plasma samples obtained over a 24-h interval: baseline (pre-administration) and at 14 different times within the 24 h after administration. The analytical method, which used HPLC coupled with a MS/MS detector, was duly validated and the analytical assay was performed in compliance with Good Laboratory Practice (GLP). The limit of quantification (LOQ) was 0.50 ng/mL. Pharmacokinetic parameters representing the extent and/or rate of absorption (AUCinf, AUClast, and Cmax) were obtained. As secondary objective the tolerability of both formulations was also evaluated. RESULTS: The geometric mean of the test/reference formulations individual percent ratio was 98.14 % for AUCinf, 98.44 % for AUClast and 98.39 % for Cmax. The 90 % CI for the geometric mean of the individual ratio test/references formulations was 95.13 to 101.24 % for AUCinf, 95.23 to 101.76 % for AUClast, and 88.26 to 109.67 % for Cmax. CONCLUSIONS: The 90 % CI values obtained for AUCinf, AUClast, and Cmax are within the interval proposed by the EMEA/CPMP and the FDA as bioequivalence acceptance criteria, and consequently it can be conclude that the test formulation is bioequivalent with the reference formulation both in terms of rate and extent of absorption after single dose administration. The results from a previous pilot study allowed an optimal design for this trial.     

Bioequivalence study of two different film-coated tablet formulations of losartan-hydrochlorothiazide in healthy volunteers

The study was conducted in order to assess the bioequivalence of two film-coated formulations containing 100 mg of losartan (CAS 124750-99-8) and 12.5 mg of hydrochlorothiazide (CAS 58-93-5). Seventy-three healthy subjects were enrolled in a randomised, single-dose, open-label, two-way crossover study, with a minimum washout period of 7 days. A total of 21 blood samples were collected up to 36 h post-dosing. Losartan, losartan carboxy acid and hydrochlorothiazide levels were determined by liquid chromatography with tandem mass detection (lower limit of quantification: 1.01 ng/mL for hydrochlorothiazide, 2.02 ng/mL for losartan and 2.51 ng/mL for losartan carboxy acid). Pharmacokinetic parameters used for bioequivalence assessment (AUC(0-t) and Cmax as primary and AUC(0-inf) as secondary pharmacokinetic parameters) were determined from the losartan and hydrochlorothiazide concentration data using non-compartmental analysis. Data from losartan carboxy acid was reported and presented as supportive data. The 90% confidence intervals (obtained by ANOVA) for losartan were 97.05-118.48% for Cmax 100.76-106.10% for AUC(0-t) and 100.80-106.10% for AUC(0-inf) whereas for hydrochlorothiazide the 90% confidence intervals obtained were 103.94-115.33% for Cmax, 101.97-109.61% for AUC(0-t) and 101.77-109.02% for AUC(0-inf), and for losartan carboxy acid the intervals obtained were 98.31-107.82% for Cmax, 97.89-104.30% for AUC(0-t) and 98.06-104.30% for AUC(0-inf). All the 90% confidence intervals obtained for all the parameters assessed were within the predefined ranges (80-125%). Based on these results, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.     

Bioequivalence study of two tablet formulations of sildenafil

This study was conducted in order to assess the bioequivalence of two tablet formulations containing 100 mg sildenafil (1-[4-ethoxy-3-(6,7-dihydro-1-,ethyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulphonyl] -4-methyl piperazine, CAS 139755-83-2). Twenty-eight healthy subjects were enrolled in a single-centre, randomised, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected up to 18.0 h postdosing. Sildenafil levels were determined by reverse liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS). Pharmacokinetic parameters used for bioequivalence assessment [area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(last)) and maximum observed concentration (C(max)) were main evaluation criteria; however, the area under the concentration-time curve from time zero to infinity (AUC(inf)) was also analysed] were determined from the sildenafil concentration data using non-compartmental analysis. The 90% confidence intervals (obtained by analysis of variance, ANOVA) were 86.70-108.19 for C(max), 86.67-99.26 for AUC(last) and 87.19-99.82 for AUC(inf) within the predefined ranges. Bioequivalence between the two formulations was concluded both in terms of rate and extent of absorption.     

Bioequivalence study of two different coated tablet formulations of finasteride in healthy volunteers

This study was conducted in order to assess the bioequivalence of two different coated tablet formulations containing 5 mg finasteride (CAS 98319-26-7). Twenty-six healthy volunteers were enrolled in an open, randomised, crossover single dose study with 2 periods x 2 sequences and a minimum washout period of 7 days. Plasma samples were obtained over 24 h (at baseline, +0.5 h, +1 h, +1.5 h, +2 h, +2.5 h, +3 h, 3.5 h, +4 h, +4.5 h, +5 h, +6 h, +8 h, +10 h, +12 h, +16 h and +24 h after administration). Finasteride levels were determined by high-pressure liquid chromatography with tandem mass detection, HPLC-MS/ MS, (LOQ 0.50 ng/mL). Pharmacokinetic parameters used for bioequivalence assessment (AUClast and Cmax were main evaluation criteria, however, AUCinf was also analysed) were determined from the finasteride concentration data using non-compartmental analysis. The 90 % confidence intervals (obtained by ANOVA) were 86.31-98.69 for Cmax, 95.40-104.88 for AUClast and 96.20-105.81 for AUCinf that is, they were all within the predefined ranges. It may be therefore concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.     

Bioequivalence of clarithromycin tablet formulations assessed in Korean males

AIM: Determination of the bioequivalence of 2 clarithromycin tablet formulations manufactured in Korea. PATIENTS AND METHODS: Twenty-four healthy male Korean volunteers received each of the 2 clarithromycin formulations at a dose of 250 mg in a 2 x 2 crossover study. There was a one-week washout period between doses. Plasma concentrations of clarithromycin were monitored by high-performance liquid chromatography over a period of 12 hours after administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated using the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax and untransformed Tmax. RESULTS: The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were 0.971 (0.886 approximately 1.063) and 0.982 (0.868 approximately 1.107), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. The corresponding value of Tmax was 0.000 (-0.250 approximately 0.250). CONCLUSION: These results indicate that the 2 medications of clarithromycin are bioequivalent and, thus, may be prescribed interchangeably.     

Bioequivalence of ciprofloxacin tablet formulations assessed in Indonesian volunteers

AIM: Determination of the bioequivalence of two ciprofloxacin tablet formulations (test formulation manufactured by Novell Pharmaceutical Laboratories, Indonesia, reference formulation from Quimica Farmaceutica Bayer, Spain). SUBJECTS AND METHODS: 24 healthy volunteers received each of the two ciprofloxacin formulations at a dose of 500 mg in a 2-way crossover design. Blood samples were obtained prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and24h after drug administration. Plasma concentrations of ciprofloxacin were monitored using high-performance liquid chromatography over a period of 24 h after administration. The pharmacokinetics parameter AUC0-24h, AUC0-infinity and Cmax were tested for bioequivalence after log-transformation of data and ratios of tmax were evaluated non-parametrically. RESULTS: The point estimates and 90% confidence intervals for AUC0-24h, AUC0-infinity and Cmax were 97.55% (92.71 - 102.6%), 97.63% (92.90 - 102.59%) and 95.84% (89.95 - 102.10%), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. CONCLUSION: These results indicate that two medications of ciprofloxacin are bioequivalent and, thus, may be prescribed interchangeably.     

Bioequivalence of pravastatin tablet formulations assessed in Korean males

AIM: Determination of the bioequivalence of 2 pravastatin tablet formulations manufactured in Korea. PATIENTS AND METHODS: Twenty-three healthy male Korean volunteers received each of the 2 pravastatin formulations at a dose of 20 mg in a 2 x 2 crossover study. There was a 1-week washout period between doses. Plasma concentrations of pravastatin were monitored using high-performance liquid chromatography over a period of 8 hours after administration. AUC(0-8h) (the area under the plasma concentration-time curve from time zero to the last measured time in plasma, 8 h) was calculated using the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC(0-8h) and Cmax and untransformed tmax. RESULTS: The point estimates and 90% confidence intervals for AUC(0-8h) (parametric) and Cmax (parametric) were 1.067 (0.968 to approximately 1.176) and 1.074 (0.999 to approximately 1.155), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. The corresponding value of tmax was 0.000 (-0.250 to approximately 0.250). CONCLUSION: These results indicate that the 2 medications of pravastatin are bioequivalent and, thus, may be prescribed interchangeably.     

Bioequivalence study of two perindopril erbumine tablet formulations in healthy volunteers

The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 20 healthy adult male and female subjects under fasting conditions. In this study, one subject withdrew from the study and one reserve subject did not appear at both periods. The pharmacokinetic parameters were assessed based on the concentrations of perindopril (CAS 82834-16-0) and perindoprilat (CAS 95153-31-4) because perindopril has litte pharmacologic activity until hydrolized in the liver into its active metabolite, perindoprilat. The blood samples from 18 subjects were analyzed for plasma concentrations of perindopril and perindoprilat. In each of the two study periods (separated by a washout of three weeks) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 192 h (AUC), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t(1/2)). The geometric mean ratios (90% CI) of the test drug/reference drug for perindopril and perindoprilat were 106.59% (92.97-122.20%) and 100.56% (94.11-107.46%) for AUC,, 106.64% (93.39-121.77%) and 100.88% (95.30-106.80%) for AUCinfo, and 101.23% (87.39-117.27%) and 99.30% (90.42-109.05%) for Cmax, respectively. The 90% confidence intervals calculated for AUCt and Cmax of perindopril and perindoprilat were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two perindopril erbumine tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.     

Bioequivalence study of two clopidogrel film-coated tablet formulations in healthy volunteers

The present study was performed to compare the bioavailability of two clopidogrel 75 mg film-coated tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 24 healthy adult male and female subjects under fasting condition. The pharmacokinetic parameters were assessed based on the concentrations of clopidogrel (CAS 120202-66-6) parent compound. In each of the two study periods (separated by a washout of one week) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 24 h (AUCt), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax), time needed to achieve the peak plasma concentration (t(max)), and the elimination half life (t1/2). The geometric mean ratios (90% CI) of the test drug/reference drug for clopidogrel parent compound were 95.19% (81.63-110.90%) for AUCt, 95.55% (80.50-113.42%) for AUCinf, and 100.18% (80.87-124.09%) for Cmax. The 90% confidence intervals calculated for AUCt and Cmax of clopidogrel parent compound were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two clopidogrel film-coated tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.     

Bioequivalence studies of film-coated tablet and chewable tablet generic formulations of montelukast in healthy volunteers

Two studies were conducted in order to assess the bioequivalence of montelukast (CAS 151767-02-1) 10 mg film-coated tablet (FCT) and 5 mg chewable tablet (CT) test formulations in comparison with the original brands. Under fasting conditions, healthy male and female volunteers received one 10 mg FCT or 5 mg CT orally as a single dose of a test or reference formulation. Both studies were designed as open-label, randomized, two-period, two-sequence, crossover studies with a 7-day washout interval. Plasma samples were collected up to 24 h after drug administration and montelukast levels were determined by a validated LC/ MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental analysis and were statistically compared by analysis of variance for test and reference formulation. Bioequivalence between products was determined by calculating 90% confidence interval of the ratio test/reference of least-square means of logarithmically transformed Cmax and AUC0-t parameters. AUC0-infinity was also analysed to obtain additional information. The calculated 90% confidence intervals for the ratios of Cmax and AUC0-t parameters were 89.33-110.52 and 92.06-109.46, respectively, in the FCT study, and 91.58-101.86 and 92.15-98.83, respectively, in the CT study, which are all within the bioequivalence acceptance range of 80-125%. Based on the results, it can be concluded that the evaluated test FCT and CT formulations are bioequivalent to their respective reference formulation in terms of rate and extent of absorption.     

Bioequivalence assessment of two different tablet formulations of diltiazem after single and repeated doses in healthy subjects

The study was performed on 14 healthy volunteers in order to compare the pharmacokinetics and hence assess the bioequivalence of two different tablet formulations of diltiazem administered orally. The study was carried out after single doses (60 mg) and repeated doses (60 mg three times a day for six days and 60 mg on the seventh day) according to a randomised, cross-over, open design. The pharmacokinetic parameters AUC0-infinity (ng h/ml), Tmax(h) and Cmax (ng/ml) were calculated for the two formulations after a single dose, while AUCt1-t2 (= AUC for a repetitive dose interval or dosing cycle, ng h/ml) and PTF (peak trough fluctuation) were calculated after repeated doses. The bioequivalence assessment was the shortest 90% confidence interval for the ratio (difference) of expected medians in the respective bioequivalence range (0.80-1.20). The results of this study show that, after either a single dose or repeated doses of test or reference formulations of diltiazem, the pharmacokinetics of the two formulations are similar. The ratios of AUC on day 1 (for single-dose treatment) and on day 7 (for repeated-dose treatment), and the corresponding 90% confidence intervals demonstrate bioequivalence between the two formulations of diltiazem within the accepted range of 0.80-1.20 (80-120%).     

Bioequivalence assay between orally disintegrating and conventional tablet formulations in healthy volunteers

The purpose of this study was to evaluate bioequivalence of two commercial 8 mg tablet formulations of ondansetrona available in the Brazilian market. In this study, a simple, rapid, sensitive and selective liquid chromatography-tandem mass spectrometry method is described for the determination of ondansetron in human plasma samples. The method was validated over a concentration range of 2.5-60 ng/ml and used in a bioequivalence trial between orally disintegrating and conventional tablet ondansetron formulations, to assess its usefulness in this kind of study. Vonau flash (Biolab Sanus Farmacêutica, Brazil, as test formulations) and Zofran (GlaxoSmithKline, Brazil, as reference formulation) were evaluated following a single 8 mg dose to 23 healthy volunteers of both genders. The dose was administered after an overnight fast according to a two-way crossover design. Bioequivalence between the products was determinated by calculating 90% confidence interval (90% CI) for the ratio of C(max), AUC(0-t) and AUC(0-infinity) values for the test and reference products, using logarithmically transformed data. The 90% confidence interval for the ratio of C(max) (87.5-103.8%), AUC(0-t) (89.3-107.2%) and AUC(0-infinity) (89.7-106.0%) values for the test and reference products is within the 80-125% interval, proposed by FDA, EMEA and ANVISA. It was concluded that two ondansetron formulations are bioequivalent in their rate and extent of absorption.     

Bioequivalence of two thorazine tablet formulations using radioimmunoassay and gas chromatographic-mass spectrometric methods

Two analytical methods for the analysis of chlorpromazine (CPZ), a radioimmunoassay (RIA) and a GLC-MS method, were compared in a bioequivalence study of two CPZ tablet formulations (Thorazine: film coated and sugar coated). Thirty-six nonsmoking, healthy, male volunteers completed the study. Each subject ingested single doses (2 x 25 mg) of the test (T) and the reference (R) formulations in a two-way crossover design with a two-week drug-free interval between doses. Following each administration, plasma concentrations of CPZ were monitored over a period of 24 h by both RIA and GLC-MS methods. Plasma concentrations and pharmacokinetic parameters determined by either analytical method showed wide intersubject variation, with the GLC-MS data showing relatively higher magnitude of intersubject variation than the RIA data. In general, plasma concentrations measured by RIA were significantly different from those measured by GLC-MS (paired t tests: p less than 0.0001). As indicated by the regression analysis, concentrations determined by RIA were 1.3-1.4 times higher than those determined by GLC-MS. There were strong and significant correlations between the two methods for both T and R (r greater than 0.75: p less than 0.0001). Similar statistical relationships were found between the plasma concentrations of CPZ determined by the two methods at each sampling time and the bioequivalence parameters area under the plasma level versus time curves up to the last measurable concentration (AUCt0) and the maximum plasma concentration (Cmax).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of pipamperone from three different tablet formulations

Twenty-four (24) Caucasian male subjects completed a single-blind, randomised, three-treatment, three-period, cross-over study. In each treatment phase, subjects received a single dose of 144 mg pipamperone dihydrochloride (CAS 2448-68-2) (equivalent to 120 mg pipamperone; CAS 1893-33-0) as either the reference product (3 x 40 mg tablets), test product A (3 x 40 mg tablets) or test product B (1 x 120 mg tablet). Each consecutive dosing was separated by a washout period of 14 days. Following each dosing, venous blood samples were collected over a period of 120 h for the determination of plasma pipamperone concentrations by high-performance liquid chromatography. The most common drug related adverse events, ranging from mild to moderate in intensity, were bloodshot eyes, nasal congestion, dry mouth, hypotension and dizziness. The geometric mean Cmax of pipamperone for both the reference product and test product A was 266 ng/ml and for test product B 263 ng/ml. The geometric mean AUC0-infinity was 3107 ng.h/ml for the reference product, 3229 ng.h/ml for test product A and 3108 ng.h/ml for test product B. The two test products were shown to be bioequivalent to the reference product with respect to all pharmacokinetic variables investigated.     

Bioequivalence of a prednisolone tablet administered as a single oral dose in healthy male volunteers

OBJECTIVE: A bioequivalence study ofprednisolone as Nisolone (test) tablets versus Delta-Cortef (reference) tablets was conducted. PATIENTS AND METHODS: Eighteen healthy male Korean volunteers received both 20 mg formulations of prednisolone in this 2 x 2 crossover study with a 1-week washout period between the doses. Plasma concentrations of prednisolone were monitored over a period of 12 hours after the administration using high-performance liquid chromatography. The AUC (area under the plasma concentration-time curve from time zero to infinity) and AUCt (area under the plasma concentration-time curve from time zero to the last sampling time) were calculated using the trapezoidal rule-extrapolation method. The Cmax (maximum plasma drug concentration) and t(max) (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC, AUCt and Cmax and untransformed t(max). RESULTS: The geometric mean of AUCt was 1,786 ng/ml x h (test medication) and 1,787 ng/ml xh (reference medication). A Cmax of 409 ng/ml and 404 ng/ml was achieved for the test and the reference medication, respectively. Point estimates and 90% confidence intervals for AUCt (parametric) and Cmax (parametric) were 0.989 (0.942 approximately 1.039) and 1.013 (0.934 approximately 1.100), respectively. These results satisfy the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of t(max) was -0.221 (-0.415 approximately 0.000). CONCLUSION: The 2 medications of prednisolone examined are bioequivalent and, thus, may be prescribed interchangeably.