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.     

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 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.     

Bioequivalence study of two esomeprazole enteric coated formulations in healthy Chinese volunteers

A bioequivalence study of two esomeprazole (CAS 119141-88-7) enteric-coated formulations was carried out in 20 healthy Chinese volunteers according to a single dose, two-sequence, crossover randomized design. The two formulations were administered in two treatment days, separated by a washout period of 7 days. Blood samples were collected at specified time intervals over 10 h post-dosing. Plasma samples were separated and assayed for esomeprazole using a selective and sensitive HPLC method with UV detection. The pharmacokinetic parameters AUC(0-12h), AUCmax, Cmax, tmax, t1/2 and MRT were determined from the plasma concentration-time profile of both formulations. ANOVA and two one-sided t-test procedures showed no significant difference in log-transformed Cmax, AUC(0-12h) and AUC(0-infinity) while the 90% confidence interval (CI) of the ratio of the geometric means of their values were also used to assess bioequivalence between the two formulations. The results of this study indicated that the two esomeprazole formulations can be 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.     

Esomeprazole MUPS 40 mg tablets and esomeprazole MUPS 40 mg tablets encapsulated in hard gelatine are bioequivalent

OBJECTIVE: To investigate the bioequivalence of esomeprazole MUPS 40 mg tablets administered with and without a hard gelatine capsule. MATERIAL AND METHODS: Bioequivalence of the esomeprazole MUPS 40 mg tablet administered without (Reference) and with a hard gelatine capsule (Test) was evaluated using a randomized, two-period crossover study. In each study period 49 healthy male Caucasian subjects received a single oral dose of 40 mg esomeprazole. Blood samples were collected at specified time intervals, and serum was separated and analyzed for esomeprazole concentrations using a validated HPLC-MS method. The primary parameters were AUC (extent of absorption) and Cmax (rate of absorption). The time-to-peak plasma concentration, tmax, and the elimination half-life, t1/2, were determined as secondary characteristics. Point estimates and 90%-confidence intervals were obtained for the ratio of the population medians of Test and Reference, using a multiplicative model and a parametric analysis except in the case of tmax, where an additive model and a non-parametric analysis was used. Bioequivalence of Test and Reference was concluded if the 90%-confidence intervals were entirely within the predefined equivalence ranges. RESULTS: The AUC(0-infinity) and Cmax-ratios (Test/Reference) were 1.00 and 1.01, respectively. The 90%-confidence intervals for AUC(0-infinity) (0.94-1.06) and Cmax (0.93-1.09) of these ratios were within the predefined equivalence range of 0.80-1.25 and 0.75-1.33, respectively. The ratios and 90%-confidence intervals of the secondary characteristics t1/2 and tmax were also within the respective predefined equivalence ranges. Both esomeprazole formulations were well tolerated and safe. CONCLUSION: The encapsulation of esomeprazole MUPS 40 mg tablets does not influence the extent and rate of absorption assessed by using AUC(0-infinity) and Cmax. Thus, bioequivalence could be demonstrated.     

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.     

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.     

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.     

Fluoxetine bioequivalence study: quantification of fluoxetine and norfluoxetine by liquid chromatography coupled to mass spectrometry.

In this study, the authors assessed the bioequivalence of two fluoxetine tablet formulations in 24 healthy volunteers of both sexes who received a single 20 mg dose of each fluoxetine formulation, and a new sensitive method for the quantification of fluoxetine and norfluoxetine in human plasma was developed. The study was conducted using an open, randomized, two-period crossover design with a 4-week washout interval. Plasma samples were obtained over a 672-hour period. Plasma fluoxetine and norfluoxetine concentrations were analyzed by combined liquid chromatography coupled to mass spectrometry (LC-MS) with positive ion electrospray ionization using selected ion recording (SIR). Kolmogorov-Smirnov's test, histograms, probit plots, and the correlation between norfluoxetine AUC(0-infinity) and fluoxetine AUC(0-infinity) were used to analyze the population distribution. The limit of quantification was 0.15 ng.ml-1 and 0.50 ng.ml-1 for both fluoxetine and norfluoxetine, respectively. Within- and between-run imprecision was less than 13% and 17%, respectively. The pharmacokinetic parameters obtained for fluoxetine and norfluoxetine after the administration of each formulation included AUC(0-672 h), AUC(0-infinity), Cmax, Cmax/AUC(0-672 h), tmax, t1/2, and Ke. The AUC values for fluoxetine were not consistent with a normal distribution, reflecting the existence of two different populations (poor and extensive metabolizers). The mean pharmacokinetic parameters for extensive fluoxetine metabolizers were 27.0 ng ml-1 for Cmax, 2064.0 ng h ml-1 for AUC(0-infinity), and 85.4 h t1/2. The mean pharmacokinetic parameters for norfluoxetine (in extensive metabolizers only) were 2532.0 ng h ml-1 for AUC(0-infinity) and 8.4 ng ml-1 for Cmax. For fluoxetine bioequivalence, the 90% CI of the individual ratio geometric mean for Psiquial/Prozac (including both extensive and poor metabolizers) was 101.6% to 121.1% for AUC(0-672 h) and 86.1% to 102.6% for Cmax. For norfluoxetine, the 90% CI of the individual ratio geometric mean for Psiquial/Prozac (including both extensive and poor metabolizers) was 90.3% to 108.3% for AUC(0-672 h) and 84.5% to 106.3% for Cmax. The new method developed (LC-MS) presented high sensitivity, specificity, and short chromatographic run for the quantification of both fluoxetine and norfluoxetine in human plasma. Since both 90% CI for AUC and Cmax geometric mean ratios were included in the 80% to 125% interval proposed by the U.S. Food and Drug Administration, Psiquial was considered bioequivalent to Prozac according to both the rate and extent of absorption. The finding that there were no significant differences in the bioequivalence assessed by either fluoxetine or norfluoxetine pharmacokinetic parameters indicates that future bioequivalence trials may be performed by quantifying fluoxetine only.     

Bioequivalence evaluation of two rabeprazole enteric coated formulations in healthy Chinese volunteers.

A bioequivalence study of two rabeprazole enteric-coated formulations was carried out in 20 healthy Chinese volunteers according to a single dose, two-sequence, crossover randomized design. The two formulations were administered in two treatment days, separated by a washout period of 7 days. Blood samples were collected at specified time intervals over 10 hours post-dosing. Plasma samples were separated and assayed for rabeprazole using a selective and sensitive HPLC method with UV detection. The pharmacokinetic parameters AUC(0-T), AUCmax, Cmax, tmax, t(1/2) and MRT were determined from plasma concentration-time profile of both formulations. ANOVA and two one-sided t test procedures showed no significant difference in log-transformed Cmax, AUC(0-T) AUC(0-infinity) while the 90% confidence interval (CI) of the ratio of the geometric means of their values were also used to assess bioequivalence between the two formulations. The results of this study indicated that the two rabeprazole formulations can be considered to be bioequivalent.     

Bioavailability investigation of two different oral formulations of methylprednisolone

Two different oral methylprednisolone (CAS 83-43-2) formulations (Methylprednisolon-ratiopharm 8 mg tables as test preparation (T) and tablets of a reference preparation (R)) were investigated in 16 healthy volunteers in order to prove bioequivalence between these preparations. A single 8 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of methylprednisolone plasma concentrations were collected at pre-defined time points up to 16 h following drug administration. A washout period of 3 days separated both treatment periods. Methylprednisolone plasma concentrations were determined by means of a validated HPLC method. Values of 342.53 ng.h/ml (test preparation) and 336.61 ng.h/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 66.58 ng/ml and 70.51 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 2.2 h for both preparations. Cmax and AUC0-infinity-values were tested parametrically by the two one-sided t-test procedure. Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80-125% for AUC0-infinity and 70-143% for Cmax. Based on the results obtained in this study, bioequivalence between Methylprednisolone ratiopharm and the reference preparation was demonstrated.     

Bioavailability investigation of two different oral formulations of Tetrazepam

Two different oral tetrazepam (CAS 10379-14-3) formulations (Tetrazepam-ratiopharm film-coated tablets as test preparation and tablets of a reference preparation marketed in France) were investigated in 20 healthy volunteers in order to prove bioequivalence between these preparations. A single 50 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of tetrazepam plasma concentrations were collected at pre-defined time points up to 96 h following drug administration. A washout period of 14 days separated both treatment periods. Tetrazepam plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 3873.08 ngh/ml (test preparation) and 3930.69 ngh/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 482.08 ng/ml and 465.14 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 1.39 hours for both preparations. Cmax and AUC0-infinity-values were tested parametrically by an analysis of variance (ANOVA). Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for AUC0-infinity and 70%-143% for Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.     

Pharmacokinetics and bioequivalence evaluation of 2 levosulpiride preparations after a single oral dose in healthy male Korean volunteers

OBJECTIVE: To evaluate the bioequivalence of a single oral 25 mg dose of 2 levosulpiride preparations in healthy male Korean volunteers. SUBJECTS, MATERIALS AND METHODS: The study was conducted as a randomized, 2-period crossover design in 28 healthy male Korean volunteers who received a single oral dose of 25 mg levosulpiride tablet in each study period. There was a 6-day washout period between the doses. Serum concentrations of levosulpiride up to 36 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), Cmax (maximum serum concentration), tmax (time to reach Cmax) and t1/2 (terminal half-life) were analyzed by non-compartmental analysis, and the analysis of variance (ANOVA) was carried out using logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax, and untransformed Tmax. RESULTS: In vitro dissolution profiles were similar by calculating similarity factor (f2 = 67.73). There were no significant differences between the 2 preparations in AUC(0-t), AUC(0-infinity) and Cmax. The point estimates (90% confidence intervals) for AUC(0-t), AUC(0-infinity) and Cmax were 1.085 (1.003-1.173), 1.069 (0.991-1.153) and 1.075 (0.954 to 1.210), 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 2 preparations of levosulpiride are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.     

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.     

Bioavailability investigation of two different oral formulations of doxepin

Two different oral doxepin (CAS 1668-195) formulations (Doxepin-ratiopharm 25 mg film-coated tablets as test preparation and 25 mg dragées of the reference preparation) were investigated in 30 healthy male and female volunteers in order to prove bioequivalence between these preparations. A single 75 mg oral dose (3 units of test or reference preparation) was given according to a randomised two-way cross-over design in the fasted state. Blood samples for determination of plasma concentration of doxepin and its metabolite N-desmethyldoxepin were collected at pre-defined time points up to 168 h following drug administration. A wash-out period of three weeks separated both treatment periods. Doxepin and N-desmethyldoxepin plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 193,463 pgh/ml (test preparation) and 197,988 pg h/ml (reference preparation) for doxepin as well as values of 313,298 pg h/ml (test preparation) and 306,663 pgh/ml (reference preparation) for N-desmethyldoxepin for the parameter AUC0-infinity demonstrate a nearly identical extent of drug absorption. Maximum concentrations (Cmax) for doxepin/N-desmethyldoxepin of 15,960.06/6,883.69 pg/ml and 18,614.73/6,846.62 pg/ml were achieved for test and reference preparation. Time to reach doxepin maximum plasma concentration (tmax) was 1.98 h for both preparations and for N-desmethyldoxepin tmax was 4.52 h (test preparation) and 4.15 h (reference preparation). Cmax and AUC0-infinity values were tested for statistically significant differences by means of the Two One-Sided T-Tests procedure following ln-transformation of data. Bioequivalence was assumed if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for ln-transformed AUC0-infinity and 70%-143% for ln-transformed Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.     

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 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 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.