Pharmacokinetics and bioequivalence evaluation of two gabapentin preparations after a single oral dose in healthy Korean volunteers

OBJECTIVE: To evaluate the bioequivalence of a single oral 400 mg dose of 2 gabapentin preparations in healthy male Korean volunteers. SUBJECTS, MATERIALS AND METHODS: The study was conducted as a randomized, 2-period crossover design in 26 healthy male Korean volunteers who received a single oral dose of 400 mg gabapentin capsule in each study period. There was a 7-day washout period between the doses. Serum concentrations of gabapentin up to 24 hours after the administration were determined using a validated HPLC method with fluorescence detection. In addition, in vitro dissolution profiles of both preparations were examined. The pharmacokinetic parameters such as AUC(0.t) (the area under the curve from zero to the time), AUC(0-infinity) (the area under the curve from zero to infinity), C(max) (maximum serum concentration), t(max) (time to reach C(max)) and t1/2 (terminal half-life) were analyzed by noncompartmental analysis, and the analysis of variance (ANOVA) was carried out using logarithmically transformed AUC(0-t), AUC(0-infinity) and C(max) and untransformed t(max). RESULTS: In vitro dissolution profiles were very similar at all media. There were no significant differences between the two preparations in AUC(0-t), AUC(0-infinity) and C(max). The point estimates (90% confidence intervals) for AUC(0-t), AUC(0-infinity) and C(max) were 1.0319 (0.9142 - 1.1647), 1.0127 (0.8458 - 1.2127) and 0.9796 (0.8670 - 1.1069), respectively, satisfying the bioequivalence criteria of 0.80 - 1.25 as proposed by the US FDA and the Korean legislation. No statistically significant difference was found for tmax and t1/2 values. CONCLUSION: From the results of the present study, it is indicated that the two preparations of gabapentin are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.     

Comparative bioavailability of two immediate-release tablets of lisinopril/hydrochlorothiazide in healthy volunteers

AIM: Two formulations of lisinopril/hydrochlorothiazide (20 mg/12.5 mg) were evaluated for bioequivalence after single dosing in healthy volunteers. METHODS: The study was conducted according to an open, randomized, 2-period crossover design with a 2-week washout interval between doses. Twenty-four volunteers participated and all completed the study successfully. Lisinopril and hydrochlorothiazide were determined in plasma by HPLC. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were tested for bioequivalence after logarithmic transformation of data and ratios of tmax were evaluated non-parametrically. RESULTS: For lisinopril, the parametric analysis revealed the following test/reference ratios and their confidence intervals (90% CI): 1.01 (0.84-1.22) for AUC(0-t), 0.98 (0.81-1.19) for AUC(0-infinity), 1.02 (0.83-1.25) for Cmax and 1.03 (0.99-1.08) for Cmax/AUC(0-infinity). The 90% CI for tmax was 0.94-1.07. All parameters showed bioequivalence between both formulations. As for hydrochlorothiazide, test/reference ratios and their confidence intervals (90% CI) were: 1.05 (0.95-1.17), 1.02 (0.93-1.12) for AUC(0-infinity), 0.99 (0.89-1.07) for Cmax and 0.97 (0.90-1.04) for Cmax/AUC(0-infinity). The 90% CI for tmax was 1.00-1.41. All parameters showed bioequivalence between both formulations except for tmax. A discrete fall in both systolic (SBP) and diastolic (DBP) blood pressure was observed after drug administration. The time course of both parameters was similar for the 2 formulations. Heart rates also followed a similar time profile. CONCLUSIONS: The bioequivalence of the 2 formulations of lisinopril/hydrochlorothiazide was demonstrated.     

Bioequivalence of two oral ciprofloxacin tablets formulations

The relative bioavailability of a new 750 mg tablet formulation of ciprofloxacin (test formulation supplied by Dr. August Wolff GmbH and Co., Germany) was compared with that of Ciprobay tablets 750 mg (reference formulation from Bayer Vital GmbH and Co., Germany). Twenty-four healthy volunteers (12 male and 12 female) were included in this single-dose, 2-sequence, crossover randomized study. Blood samples were obtained prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24 and 30 hours after drug administration. Plasma concentrations of ciprofloxacin were determined by HPLC. No differences were found when the in vitro dissolution profiles of both formulations were compared. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were tested for bioequivalence after log-transformation of data, and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following mean values for the test/reference ratios (90% standard confidence intervals in parenthesis (ln-transformed data): 1.01 (0.95-1.07) for AUC(0-t), 0.99 (0.93-1.05) for AUC(0-infinity), 1.05 (0.97-1.14) for Cmax and 1.06 (0.97-1.15) for Cmax/AUC(0-infinity). The nonparametric confidence interval for tmax was 0.77-1.15. All parameters showed bioequivalence between both formulations as their confidence intervals were within the bioequivalence acceptable range of 0.80-1.25 limits; the 90% confidence interval for tmax slightly exceeded limits of bioequivalence. We conclude that both formulations show bioequivalence for both the rate and the extent of absorption.     

Bioequivalence study of two capsule formulations containing diacerein 50 mg in healthy human subjects

This study presents the results of a two-way, two-period, two-treatment crossover investigation in 12 healthy Indian male subjects to assess the bioequivalence of two oral formulations containing 50 mg of diacerein (CAS 13739-02-1). Both formulations were administered orally as a single dose separated by a one-week washout period. The content of diacerein in plasma was determined by a validated HPLC method with UV detection. The formulations were compared using the parameters area under the plasma concentration-time curve (AUC(0-t)), area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)), peak plasma concentration (Cmax), and time to reach peak plasma concentration (tmax). The results of this study indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity) and Cmax, values of the two preparations. The 90% confidence interval for the ratio of the logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax were within the bioequivalence limit of 0.8-1.25 and the relative bioavailability of the test formulation was 96.63% of that of the reference formulation. Thus, these findings clearly indicate that the two formulations are bioequivalent in terms of rate and extent of drug absorption.     

Comparative bioavailability study of doxycycline hyclate (equivalent to 100 mg doxycycline) capsules (doxycin vs vibramycin) for bioequivalence evaluation in healthy adult volunteers

This investigation was carried out to evaluate the bioavailability of a new capsule formulation of doxycycline (100 mg), doxycin, relative to the reference product, vibramycin (100 mg) capsules. The bioavailability was carried out in 24 healthy male volunteers who received a single dose (100 mg) of the test (A) and the reference (B) products after an overnight fast of at least 10 hours on 2 treatment days. The treatment periods were separated by a 2-week washout period. A randomized, balanced 2-way cross-over design was used. After dosing, serial blood samples were collected for a period of 48 hours. Plasma concentrations of doxycycline were analyzed by a sensitive and validated high-performance liquid chromatography assay. The pharmacokinetic parameters for doxycycline were determined using standard noncompartmental methods. The parameters AUC(0-t), AUC(0-infinity), Cmax, K(el), t(1/2) and Cmax/AUC(0-infinity) were analyzed statistically using log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pharmacokinetic parameters: AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were within the range 80-125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis of the mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were 95.98-109.56%, 92.21 to 107.66%, 93.90-112.56%, and 96.0 to 106.91% respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) by the Schuirmann's two 1-sided t-tests. Therefore, the 2 formulations were considered to be bioequivalent.     

Bioequivalence study of two tablet formulations containing rimonabant 20 mg in healthy Indian subjects

A randomized, two-treatment and two-way crossover study on twelve healthy Indian male subjects was conducted to assess the bioequivalence of two tablet formulations containing 20 mg of rimonabant (CAS 158681-13-1). Both of the formulations were administered orally as a single dose with a 45-day washout period between two dosing sessions. The content of rimonabant in plasma was determined by a validated HPLC method with UV detection. The formulations were compared using the parameters area under the plasma concentration-time curve (AUC(0-t)), area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)), peak plasma concentration (Cmax), and time to reach peak plasma concentration (tmax). The results of this investigation indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity) and Cmax values of the two preparations. The 90% confidence interval for the ratio of the logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax were within the bioequivalence limit of 0.8-1.25 and the relative bioavailability of the test formulation was 96.62% of that of the reference formulation. Thus, these findings clearly indicate that the two formulations are bioequivalent in terms of rate and extent of drug absorption.     

Comparative bioavailability study of cefixime (equivalent to 100 mg/5 ml) suspension (Winex vs Suprax) in healthy male volunteers

This investigation was carried out to evaluate the bioavailability of a new suspension formulation of cefixime (100 mg/5 ml), Winex, relative to the reference product, Suprax (100 mg/5 ml) suspension. The bio-availability study was carried out in 24 healthy male volunteers who received a single oral dose (200 mg) of the test (A) and the reference (B) products on 2 treatment days after an overnight fast of at least 10 hours. The treatment periods were separated by a one-week washout period. A randomized, balanced two-way crossover design was used. After dosing, serial blood samples were collected over a period of 16 hours. Plasma concentrations of cefixime were analyzed using a sensitive high-performance liquid chromatographic assay. The pharmacokinetic parameters for cefixime were determined using standard non-compartmental method. The parameters AUC(0-t), AUC(0-infinity), Cmax, Kel, t1/2 and Cmax/AUC(0-infinity) were analyzed statistically using raw and log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pnfinity harmacokinetic parameters: AUC(0-t), AUC(0-infinity) Cmax, and Cmax/AUC(0-infinity) were within the range 80 - 125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax, and Cmax/AUC(0-infinity) were 88.93 - 107.10%, 89.09 - 107.11%, 89.63 - 108.58% and 96.85 - 105.29%, respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC(0-t), AUC(0-infinity), and Cmax using the Schuirmann's two one-sided t-tests. Therefore, the two formulations were considered to be bioequivalent.     

Comparative bioavailability study of two preparations of letrozole in healthy subjects

The bioavailability of a new letrozole (CAS 112809-51-5) preparation was compared with the reference preparation of the drug in 25 healthy volunteers, aged between 18 and 33. A single dose of 2.5 mg was given orally in the fasted state, using a randomized two-way, cross-over protocol. A washout period of two weeks separated both treatment periods. Blood samples were obtained at regular time intervals, until 312 h after drug administration. After solid phase extraction (SPE) letrozole plasma levels were measured by high pressure liquid chromatography that was validated before the start of the study (UV detector, fluoroletrozole as an internal standard). The limit of quantification was 1.4 nmol/ml. The following pharmacokinetics parameters were calculated from letrozole plasma concentrations: AUC(0-infinity), AUC(0-t), Cmax, tmax, F(rel), MRT, t(1/2), k(el). The confidence intervals for the statistical calculations of AUC(0-infinity), Cmax, tmax were 95 % and AUC(0-t), MRT, t(1/2), k(el) were tested by means of the unpaired t-tests procedure and after logarithmic transformation for overall significant differences using analysis of variance--three-way ANOVA. The AUC(0-infinity) ratio test/reference and the 90 % confidence interval were 99.52 %, and 94.05-107.31%, respectively. The Cmax ratio test/reference and the 90 % confidence interval were 89.18 %, and 84.48-98.60%, respectively. AUC(0-infinity) and Cmax ratios (90 % CI) were within the 80-125 % interval required for bioequivalence as stipulated in the current international regulations of the European Agency for the Evalution of Medicinal Products and the Food and Drug Administration. Therefore it is concluded that the new letrozole preparation is therapeutically equivalent to the reference preparation for both the extent and the rate of absorption after single dose administration in healthy volunteers.     

Relative bioavailability of two isosorbide dinitrate sublingual tablet formulations administered as single doses in healthy subjects

OBJECTIVE: The purpose of this study was to evaluate the relative bioavailability and bioequivalence of a test and a reference sublingual tablet each containing 5 mg of isosorbide dinitrate in healthy volunteers. METHODS: The study was conducted as an open-label, randomized, single-dose, two-period crossover design in 20 healthy volunteers with a washout period of 7 days, under fasting conditions. Plasma concentrations of the major active metabolite isosorbide 5-mononitrate were quantified, using a validated capillary gas chromatographic assay, with electron-capture detection. The pharmacokinetic parameters used to assess the bioequivalence of the two preparations were AUC(0-infinity) and AUC(0-infinity) for the extent of absorption and Cmax and tmax for the rate of absorption. RESULTS: The calculated 90% confidence intervals of the geometric mean values of the test/reference ratios were 98.2% to 103.2% (point estimate; 100.7%) for AUC(0-infinity) 96.9% to 103.8% (point estimate; 100.3%) for AUC(0-infinity), and 87.9% to 98.2% (point estimate; 92.9%) for Cmax. No statistically significant difference was found for tmax and elimination half-life (t 1/2) values. CONCLUSION: From the results of the present study, it is concluded that the test and reference isosorbide dinitrate sublingual preparations are bioequivalent in both extent and rate of absorption and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.     

In vivo pharmacokinetic-pharmacodynamic relationship and in vitro equivalence of two oral furosemide tablet formulations

A randomized, cross-over, open study of bioequivalence between two different furosemide (CAS 54-31-9) formulations was performed; simultaneously, diuretic effects (urine output, sodium, potassium and chloride excretion) were also compared. Both products meet the British Pharmacopoeia specification and the results of a previous in vitro comparative study ensure equivalence of the two dissolution curves. Twenty-four healthy volunteers (male/female) participated in the bioequivalence study. Each treatment was given as a single 40-mg tablet following an overnight fast. Furosemide concentrations in plasma (measured by HPLC) and electrolyte amounts in urine were determined up to 12 h after treatment. The pharmacokinetic parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity were tested for bioequivalence after ln-transformation of data and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following test/reference ratios and their 90% confidence intervals (90% CI): 1.06 (0.94-1.19) for AUC0-infinity, 1.12 (0.96-1.31) for Cmax, and 1.06 (0.97-1.16) for Cmax/AUC0-infinity. The 90% CI for tmax was 0.55-1.00. Bioequivalence between both formulations was concluded for all parameters except for tmax. No significant diuretic differences between both formulations (test and reference) were observed after drug administration in relation to the baseline period. Systolic and diastolic blood pressure and heart rate showed a similar time-course after the drug administration and there were no differences between both formulations. Both products were well tolerated. It can be concluded that both formulations are equivalent in vitro and in vivo.     

Bioequivalence of two oral formulations of triflusal capsules in healthy volunteers

Triflusal (CAS 322-79-2) is an antiplatelet agent related to salicylates used in several European and Latin American countries in the treatment of cardiovascular diseases. The aim of this paper was to evaluate the bioequivalence of triflusal derived from two preparations using both parent drug and metabolite pharmacokinetic data. The bioavailabolity was measured in 24 healthy male Caucasian volunteers following a single oral dose (600 mg) of the test or reference products in the fasting state. Blood samples were collected for 120 h. Plasma concentrations of triflusal and its metabolite 3-hydroxy-4-trifluoromethylbenzoic acid (HTB) were analyzed by high-performance liquid chromatography with UV and fluorescence detection, respectively. The non-compartmental method was used for pharmacokinetic analysis. Log-transformed Cmax, AUC0-t and AUC0-infinity were tested for bioequivalence using ANOVA and Schuirmann's two-one sided t-test. Tmax was analyzed by nonparametric pharmacokinetic parameters of triflusal and HTB derived from the two formulations were nearly consistent with previous observations. Triflusal parameters derived from the test and reference drug were as follows: Cmax (16.85 +/- 11.41 vs 14.48 +/- 7.22 mg/l), AUC0-t (18.43 +/- 10.91 vs 16.22 +/- 7.58 mg/l per hour), Tmax (1 range 0.25-2h vs 0.875 range 0.25-1.5 h), and t(1/2) (0.49 +/- 00.27 vs 0.76 +/- 0.64). HTB parameters after test and reference formulation administration were as follows: Cmax (68.13 +/- 23.05 vs 65.51 +/- 19.44 mg/l), AUC0-t (2748.18 +/- 971.91 vs 2877.97 +/- 881.2 h x mg/l), AUC0-infinity (3350.15 +/- 1182.62 vs 3372.49 +/- 1110.35 h x mg/l), Tmax (2 range 1-10 h vs 2 range 0.75-12 h), and t(1/2) (42.19 +/- 7.82 vs 43.13 +/- 6.56 h). 90% of confidence intervals for the test/reference ratio of Cmax AUC0-t and AUC0-infinity derived from both triflusal and HTB were found within the range of 80%-125% acceptable for bioequivalence. No significant difference was found between the Tmax values for triflusal and HTB. It was concluded that the two preparations are bioequivalent and may be prescribed interchangeably.     

Bioequivalence evaluation of two brands of lisinopril tablets by in vitro comparative dissolution test and in vivo bioequivalence test

The bioequivalence of a test formulation (Nanopril, "test") and a reference formulation ("reference") of lisinopril (CAS 83915-83-7) was demonstrated by in vivo and in vitro tests. The in vivo bioequivalence study in 26 healthy volunteers was designed as a single dose, randomized, double-blind trial with a 2-week washout period between the doses. Prior to the in vivo study, an in vitro comparative dissolution test was performed by the paddle method following the bioequivalence guidance of the Korea Food and Drug Administration (KFDA). By the results of the dissolution test it was demonstrated from the similar and rapidly dissolving patterns of the two lisinopril tablets that the two formulations were pharmaceutically equivalent. However, the in vivo bioequivalence study was required to fully evaluate the bioequivalence of the two drug products. In the in vivo bioequivalence study, the plasma samples drawn from the volunteers were analyzed utilizing a sensitive LC-MS-MS analysis method and the bioequivalence between the two drug products was assessed by statistical analysis of the log transformed mean ratios of Cmax,AUC(0-t) and AUC(0-infinity). The mean maximum concentration (Cmax) of the test and reference were found to be 60.41 +/- 20.07 ng/mL and 61.11 +/- 19.36 ng/mL, respectively. The 90% confidence intervals (C.I.) of Cmax were in the range from 0.91 to 1.08. As for the AUC(0-t) and the AUC(0-infinity), test values were 792.73 +/- 273.41 ng x mL(-1) x h, 862.74 +/- 303.81 ng x mL(-1) x h and the reference values were 841.66 +/- 286.07 ng . mL(-1) x h, 906.97 +/- 318.72 ng x mL(-1) x h, respectively. The 90% C. I. of AUC(0-t) were 0.86 to 1.01 and of AUC(0-infinity), 0.87 to 1.02 and thus were within the 80-125% interval proposed by the FDA. In addition to the 90% C.I. of the pharmaceutical parameters, a two-way ANOVA showed no significant difference between the two formulations. Based upon these statistical analyses, it was concluded that the test formulation is bioequivalent to the reference.     

Comparative bioavailability of alpha-methyldopa normal and film tablet formulations after single oral administration in healthy volunteers.

In a single dose, randomized, cross-over study, with one week of wash-out period, the relative bioavailability of Dopegyt tablets containing 250 mg alpha-methyldopa (AMD) and Presinol film tablets with identical active ingredient content was examined in 24 healthy volunteers. Since technologically two completely different preparations (a film-tablet and a non-film-tablet) having significantly different in vitro dissolution were to be compared, both preparations were compared to a third one, AMD solution (Dopegyt solution) with 250 mg/50 ml concentration. Plasma concentrations of the drug were measured for 24 hours post-dose, applying HPLC with fluorometric detection. Pharmacokinetic parameters calculated from individual data (AUC0-infinity, AUC0-t, Cmax, Cmax/AUC0-infinity, t(max)) were evaluated statistically. Wilcoxon's nonparametric test and the four-way variance analysis could not detect any significant difference at the usual a=95% probability level in these pharmacokinetic parameters of the two tablet preparations. For AUC0-infinity at the 90% probability level, the confidence interval was 0.883-1.237 (with an estimated geometric mean of 1.045), for the test/reference ratio of Dopegyt and Presinol tablets, thus the two preparations proved to be bioequivalent. The relative bioavailability of Dopegyt (test preparation) and Presinol (reference preparation) calculated from the AUC0-infinity values was 116.7+/-56.7% that also confirmed bioequivalence. The results of all the applied statistical tests suggest that Dopegyt and Presinol can be considered as bioequivalent preparations.     

Bioequivalence evaluation of two D-limonene capsule formulations in healthy Chinese volunteers

A randomized, three-period crossover study was conducted in 24 healthy Chinese male volunteers to compare the bioavailability of two brands of D-limonene (0.3 ml) capsules, and determine the plasma concentration of endogenous D-limonene in food-controlled non-treated humans. The three kinds of treatments were administration of the reference formulation, administration of the test, and non-administration. The plasma samples were analyzed by a validated GC-MS method after liquid-liquid extraction. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax, tmax, and t1/2 were determined from the concentration-time profiles for both formulations and were compared statistically to evaluate bioequivalence between the two brands. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within an acceptable range for bioequivalence. Besides, for the food-controlled non-treated volunteers, their plasma concentrations of D-limonene were detectable and kept relatively steady (2.94 +/- 1.38 ng/ml) within the sample collection period. Based on the statistical analysis, it was concluded that the two D-limonene capsule formulations were bioequivalent.     

Bioequivalence study of two limaprost alfadex 5 microg tablets in healthy subjects: moisture-resistant tablet (dextran formulation) versus standard tablet (lactose formulation)

OBJECTIVE: A study was conducted to assess the bioequivalence of two limaprost alfadex 5 microg tablets, a moisture-resistant tablet (dextran formulation) and a standard tablet (lactose formulation). MATERIALS AND METHODS: The clinical investigation was designed as a randomized, open-labeled, two-part, two-treatment, two-period crossover study, in 120 healthy male volunteers. One tablet of either formulation was administered with 200 ml of water after 10-hour overnight fast. After dosing, serial blood samples were collected for a period of 6 hours. Plasma harvested from blood was analyzed for limaprost by a validated LC/MS/MS method. The peak plasma concentration (Cmax) values and time associated with the maximal concentration (tmax) were obtained from the observed data. The elimination rate constant (lambda z) was obtained as the slope of the linear regression of the log-transformed concentration values vs. time data in the terminal phase, and the elimination half-life (t1/2) was calculated as 0.693/lambda z. The area under the curve to the last measurable point (AUC0-t) was estimated by the linear trapezoidal rule. The analysis of variance (ANOVA) was carried out using log-transformed AUC0-t, AUC0-A yen and Cmax and untransformed tmax, and 90% confidence intervals for AUC0-t and Cmax were calculated. If the 90% confidence intervals (CI) for both AUC0-t and Cmax fell fully within the interval 80 - 125%, the bioequivalence of the two formulations was established. RESULTS: The means of AUC0-t were 0.779 vs. 0.754 pg x h/ml (test vs. reference), and the means of the Cmax were 1.26 vs. 1.12 pg/ml (test vs. reference). The geometric mean ratios of the test formulation to reference formulation for AUC0-t and Cmax were 104.0 and 112.4%, respectively, and the 90% CI for AUC0-t and Cmax were 100.7 - 107.4% and 105.6 - 119.6%, respectively. Both 90% CI for AUC0-t and Cmax fell within the Ministry of Health, Labour and Welfare of Japan accepted bioequivalence range of 80 - 125%. CONCLUSIONS: Based on the results, the moisture-resistant tablet was determined to be bioequivalent to the standard tablet.     

In vitro and in vivo equivalence of two oral atenolol tablet formulations

A randomised, cross-over, open study of bioequivalence between two different atenolol (CAS 29122-68-7) tablet formulations is presented. An in vitro comparative study between the two formulations was also performed. Both products meet the USP 23 (United States Pharmacopea) specification. The values of similarity factor (f2) and difference factor (f1) obtained ensure sameness or equivalence of the two dissolution curves. Twenty-four healthy volunteers (male/female) participated in the bioequivalence study. Each treatment was given as a single 100-mg tablet following an overnight fast. Atenolol concentrations in plasma were determined up to 30 h after treatment by HPLC. The pharmacokinetic parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity were tested for bioequivalence after logarithmic transformation of data and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following test/reference ratios and their 90% confidence intervals (90% CI): 1.06 (0.99-1.13) for AUC, 1.07 (0.97-1.18) for Cmax, and 0.99 (0.94-1.07) for Cmax/AUC0-infinity. The 90% CI for tmax was 0.91-1.23. All parameters showed bioequivalence between both formulations. A discrete fall in both systolic (SBP) and diastolic (DBP) blood pressure was observed after the drug administration. The fall extent (approximately 11 mmHg in supine position) and the time course of both parameters after the drug administration was similar for both formulations. Minimal values for SBP and DBP were achieved at 6 h after the drug administration for both formulations. Heart rates were also reduced after the administration of both formulations of atenolol in a similar extent (12 b.p.m.) and following a similar time profile (i.e. maximal reductions were observed between 1 and 3 h after the drug administration). It can be concluded that both formulations are equivalent in vitro and in vivo.     

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 between omeprazole MUPS 20 mg as tablet and omeprazole MUPS 20 mg as tablet encapsulated in a hard gelatine capsule

AIMS: To investigate pharmacokinetic characteristics of omeprazole MUPS 20 mg tablets and its encapsulated form. MATERIAL AND METHODS: Bioequivalence of omeprazole MUPS 20 mg tablet (Reference) and omeprazole MUPS 20 mg tablet in a hard gelatine capsule (Test) was evaluated in a randomized, 2-period crossover study in 38 healthy male Caucasian subjects who received a single oral dose of 20 mg omeprazole in each study period. Serum concentrations of omeprazole MUPS 20 mg were measured using an HPLC assay. In addition, in vitro dissolution profiles were studied. RESULTS: Both formulations were bioequivalent as assessed by the primary pharmacokinetic characteristics AUC(0-infinity) and Cmax, the corresponding ratios (Test/Reference) being 0.97 and 0.98, respectively. Thus, the 90% CI of these ratios were within the equivalence range of 0.8 to 1.25 for AUC(0-infinity) (CI 0.90-1.04) and 0.67 to 1.50 for Cmax (Cl 0.86-1.10). The ratios of the secondary criteria, Cmax/AUC(0-infinity) and t 1/2, were also within the equivalence range. Median tmax of Reference and Test was identical. Both formulations revealed comparable dissolution profiles with high batch conformity and homogeneity releasing > 80% omeprazole within 1 hour. Both study formulations were well tolerated without relevant differences. CONCLUSION: The encapsulation of omeprazole MUPS 20 mg tablets does not influence the extent and rate of absorption as indicated by the AUC and Cmax ratios. Thus, bioequivalence could be demonstrated.     

Bioequivalence of different prednisolone tablet formulations

The relative bioavailability of different prednisolone (CAS 50-24-8) tablet formulations (Prednisolon Ferring 2, 5, and 20 mg) was investigated in comparison to a reference formulation. The study was performed in a GCP/ICH-conform manner using a randomized cross-over design in 13 healthy volunteers. With respect to the pharmacokinetic parameters Cmax (maximal prednisolone concentration), AUC0-12 h (area under the concentration-time curve until 12 h after drug intake), AUC0-infinity (area under the concentration-time curve until infinity), and t1/2 (elimination half-life time), 10 x 2 mg prednisolone tablets did not show any relevant differences as compared to the reference (1 x 20 mg) meaning that the 90% confidence intervals were within the given 0.80-1.25 limits for the decision of bioequivalence. Although not statistically significant, tmax (time to reach the maximal prednisolone plasma concentration) was 11 min shorter regarding the test preparation as compared to the reference. The pharmacokinetic parameters of 4 x 5 prednisolone tablets were also well in accordance with the reference. The most important parameters Cmax, AUC and t1/2 were within the defined limits for the acceptance of bioequivalence and, in addition, tmax did not show any significant differences. The 20 mg prednisolone tablet formulation showed almost identical parameters of Cmax, AUC, t1/2 und tmax in comparison to the reference substance. Taken together, the results of the bioavailability parameters indicate the bioequivalence of the three prednisolone test preparations as compared to the reference.     

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.