Bioequivalence study of two fluconazole capsule formulations in healthy volunteers

OBJECTIVE: To compare the bioavailability of a fluconazole 150 mg capsule formulation from Laboratório Teuto Brasileiro Ltd., Brazil (test formulation), and Zoltec 150 mg capsule from Laboratórios Pfizer Ltd., Brazil (reference formulation), in 24 volunteers of both sexes. MATERIAL AND METHODS: The study was conducted open with randomized 2-period crossover design and a 2-week washout period. Plasma samples were obtained over a 168-hour interval. Fluconazole concentrations were analyzed by combined reversed-phase liquid chromatography and tandem mass spectrometry (LC/MS/MS) with positive ion electrospray ionization using selected ion monitoring method. From the fluconazole plasma concentration vs. time curves the following pharmacokinetic parameters were obtained: AUC(last), AUC(0-inf) and C(max). RESULTS: Geometric mean of fluconazole/Zoltec 150 mg individual percent ratio was 102.6% for AUC(last), 102.2% for AUC(0-inf) and 109.4% for C(max). The 90% confidence intervals were 97.3-108.2%, 97.0-107.8%, and 103.1-116.0%, respectively. CONCLUSION: Since the 90% CI for both Cmax, AUC(last) and AUC(0-inf) were within the 80-125% interval proposed by the Food and Drug Administration, it was concluded that fluconazole 150 mg capsule was bioequivalent to Zoltec 150 mg, according to both the rate and extent of absorption.     

Bioequivalence of two lithium formulations in healthy volunteers

OBJECTIVE: The purpose of this study was to compare the maximum exposure and extent of bioavailability of two lithium carbonate (CAS 554-13-2) containing 300 mg tablet formulations (test and reference) for oral administration. METHOD: This bioequivalence study was conducted in a 2-period crossover design with a washout phase of 7 days. Plasma samples were obtained by blood sampling over 72 h in each period. Twenty-four healthy volunteers of both genders participated in the trial. Samples were analyzed by a flame atomic absorption spectrometer. Resulting Li+ concentrations were used for determination of the pharmacokinetic parameters AUC(last), AUC(inf) and C(max). RESULTS: 90 % confidence intervals for AUC(last), AUC(inf) and C(max) were 96.81-107.44%, 98.44-109.54% and 98.60-111.33%, respectively. CONCLUSION: All 90% and 95% confidence intervals were inside the limits defined by the FDA Guidance for Industry (80%-125%) and thus stated that test and reference formulation may be accepted as bioequivalent, with regard to both, maximum exposure and extent of bioavailability.     

Bioequivalence study of two capsule formulations of omeprazole in healthy volunteers

The study was conducted in order to assess the bioequivalence of two capsule formulations (test and reference) containing 20 mg of omeprazole (5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazole, CAS 73590-58-6). Fifty healthy male and female volunteers were treated in a single-centre, randomised, repeated-dose (once daily for six consecutive days), open-label, two-way crossover study, with a washout period of at least 9 days between treatments. Plasma samples were collected up to 12 h post-dosing for the determination of omeprazole by HPLC with photodiode array detector (DAD). The evaluation of bioequivalence was based on the following pharmacokinetic parameters that were calculated by standard non-compartmental methods: area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUCt) and that extrapolated to infinity (AUC) and the maximumobserved concentration (Cmax). The 90% confidence interval around the ratios (test/reference) (obtained by analysis of variance, ANOVA) were 0.92-1.04 forCmax, 0.88-1.05 for AUCt, and 0.88-1.05 for AUC, i.e., within the predefined acceptable range for the conclusion of bioequivalence. The study indicated that the test and reference formulations containing 20 mg of omeprazole are bioequivalent in terms of both the rate and extent of bioavailability.     

Bioequivalence study of two oral formulations of cefadroxil in healthy volunteers

Two different cefadroxil (CAS 50370-12-2) formulations were evaluated for their relative bioavailability in 24 healthy volunteers who received a single 500 mg oral dose of each preparation. An open, randomized clinical trial designed as a two-period crossover study with a 7-day washout period between doses was employed. Plasma samples for assessments of their cefadroxil concentration by HPLC-UV were obtained over 8 h after administration. Values of 48.94 +/- 10.18 pg x h/ml for test, and 48.51 +/- 9.02 microg x h/ml for the reference preparation AUC(0-t) demonstrate a nearly identical extend of drug absorption. Maximum plasma concentration Cmax of 16.04 +/- 4.94 microg/ml and 16.01 + 4.02 microg/ml achieved for the test and reference preparations did not differ significantly. The parametric 90% confidence intervals (CI) of the mean of the difference (test-reference) between log-transformed values of the two formulations were 96.80% to 104.51% and 92.01% to 107.00% for AUC(0-t) and Cmax, respectively. Since for both AUC(0-t) or Cmax the 90% CI values are within the interval proposed by the Food and Drug Administration, the test product is bioequivalent to the reference product for both the rate and extent of absorption after single dose administration.     

2种舒他西林片的人体生物等效性

目的：比较口服2种舒他西林片的相对生物利用度。方法：20名健康男性受试者采用随机交叉试验设计。反相高效液相色谱法测定单剂量口服2种舒他西林片750 mg后的氨苄西林、舒巴坦血药浓度。DAS程序计算药动学参数,AUC,c_(max)对数转换后进行分析。结果：口服舒他西林受试制剂和参比制剂氨苄西林的c_(max)分别是(10.8±s 1.9),(10.4±1.8)mg·L~(-1)；t_(max)分别是(0.68±0.14),(0.66±0.12)h；AUC_(0-t)分别为(22±4),(22±4)mg·h·L~(-1)；AUC_(0-∞)分别为(24±5),(23±4)mg·h·L~(-1)；t_(1/2)分别是(1.07±0.26),(1.13±0.25)h。口服舒他西林受试制剂和参比制剂舒巴坦的c_(max)分别是(7.4±1.3),(7.3±1.2)mg·L~(-1),t_(max)分别是(0.66±0.12),(0.70±0.10)h,AUC_(0-t)分别为(13.7±2.8),(13.2±2.3)mg·h·L~(-1)；AUC_(0-∞)分别为(14.2±2.9),(13.7±2.5)mg·h·L~(-1)；t_(1/2)分别是(0.97±0.19),(0.87±0.24)h。结论：2种舒他西林片具有生物等效性。     

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 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 formulations of simvastatin tablets in healthy Thai volunteers

The bioequivalence of two formulations of 10 mg tablets of simvastatin (CAS 79902-63-9), Vascor as test and a commercially available preparation as reference, in 18 healthy Thai male volunteers was assessed. In a randomized, single dose, two-period, crossover study design with a 1-week wash-out period, each subject received 4 tablets of 10-mg simvastatin tablets. Plasma samples were collected over a 24-h period after administration. Subsequently, plasma concentrations of simvastatin and its hydroxy acid metabolite were analyzed by using LC/ MS/MS. Pharmacokinetic parameters were determined by using non-compartmental analysis. The results showed that 90% confidence intervals of the peak concentration (Cmax) and the area under the concentration-time curve (AUC) of simvastatin and its hydroxy acid metabolite of reference and test were within 80 %-125%. Consequently the bioequivalence of these two preparations can be concluded.     

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 losartan formulations administered orally in healthy male volunteers

The bioavailability of a new losartan preparation (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt, CAS 114798-26-4) was compared with the reference preparation of the drug in 24 healthy male volunteers, aged between 19 and 32. The open, randomized, single-blind two-sequence, two-period crossover study design was performed. Under fasting conditions, each subject received a single oral dose of 100 mg losartan as a test or reference formulation. The plasma concentrations of losartan and its active metabolite were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-36h, AUC0-infinity, Cmax, t1/2, and Ke. Values of AUC0-infinity demonstrate nearly identical bioavailability of losartan from the examined formulations. The AUC0-infinity of losartan was 2019.92+/-1002.90 and 2028.58+/-837.45 ng x h/ml for the test and reference formulation, respectively. The AUC0-infinity of the metabolite was 10851.52+/-4438.66 and 11041.18 +/-5015.81 ng x h/ml for test and reference formulation, respectively. The maximum plasma concentration (Cmax) of losartan was 745.94+/-419.75 ng/ml for the test and 745.74+/-329.99 ng/ml for the reference product and the Cmax of the metabolite was 1805.77+/-765.39 and 1606.22 +/-977.22 ng/ml for the test and reference product, respectively. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for both losartan and its active metabolite. 90 % confidence limits calculated for Cmax and AUC from zero to infinity (AUC0-infinity) of losartan and its metabolite were included in the bioequivalence range (0.8-1.25 for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for losartan and its main active metabolite.     

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 fluoxetine capsule formulations in healthy Middle Eastern volunteers

OBJECTIVE: To assess the bioequivalence of two fluoxetine hydrochloride capsule (20 mg) formulations (Fluoxicare capsule from Pharmacare Ltd., Chemicals and Cosmetics, Ramallah, Palestine, as test formulation, and Prozac from Eli Lilly Ltd., Basingstoke, UK, as reference formulation). DESIGN AND METHODS: The study was conducted open with a randomized 2-period crossover design and a 6-week washout period. Participants were 24 healthy male volunteers aged 18-28 years, divided into 2 groups of 12 subjects. One group was given the originator drug (reference formulation), and the other was given the test formulation. Blood samples were obtained at baseline and at 14 time points during the interval 0-96 hours after drug administration. The concentrations of the samples were assayed spectrophotometrically at 220 nm using a Shimadzu 160 A UV-visible spectrometer. We calculated the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), and time of maximum plasma concentration (tmax) for each subject. Logarithmic transformation of the AUC and Cmax was used for the statistical analyses and to assess the bioavailability of the two formulations, using analyses of variance (ANOVA) and Satherwait t-tests for unequal variances. The ANOVA performed of tmax in Cmax, and in AUC provided the appropriate intra-subject variance estimates to evaluate the 90% confidence intervals for the differences between study variables after administration of the test and reference formulations. Statistical analyses were conducted on AUC 0-4 as the extrapolated part of the AUC, a truncated area approach was adapted. RESULTS: The mean pharmacokinetic parameters for both of the drugs under study were as follows: Cmax = 61.24 (+/- 12.96) ng/ml for the test formulation, and for the reference formulation Cmax = 61.39 (+/- 14.1) ng/ml, the effects were statistically equivalent. The tmax for the test formulation was 8.25 (+/- 1.7) and 7.33 (+/- 0.96) for the reference formulation. The area under the curve to infinity (AUC 0-infinity (ng, day/ml)) for the test formulation and for the reference formulation were 293.02 (+/- 52.69) and 296.15 (+/- 61.69), respectively. CONCLUSIONS: The two formulations had equivalent pharmacokinetic parameters, were well-tolerated, and their relative bioavailability was 98.94%.     

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 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 two tablet formulations of atenolol after single oral administration in healthy volunteers

The pharmacokinetic parameters of two oral formulations of 100 mg tablets of atenolol (CAS 29122-68-7; Azectol as test and another commercially available preparation as reference) were compared in an open-label, randomized, single oral dose, two-period cross-over design to 17 healthy volunteers under fasting conditions. Serial blood samples were collected prior to each administration and at 17 points within 36 h after dosing. Plasma concentrations of atenolol were measured by a validated HPLC assay with fluorometric detection. The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 94.4% to 112.9% (point estimate: 103%) for AUC0-infinity, 93.7% to 112.8% (point estimate: 103%) for AUC0-36, and 88.3% to 112.1% (point estimate: 100%) for Cmax, within the acceptance criteria for bioequivalence (80%-125%). Tmax values were analyzed by the nonparametric Wilcoxon test and the difference was not statistically significant. Therefore, it is concluded that the test and reference atenolol formulations are bioequivalent for both the extent and the rate of absorption.     

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 assessment of two capsule formulations of omeprazole in healthy volunteers

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two omeprazole (CAS 73590-58-6) capsule formulations, Emilok (test) and a commercially available original preparation (reference), under fasting conditions. A 20 mg dose of each formulation was administered to 36 healthy male volunteers with one-week washout period, 17 blood samples were collected over 12 h, plasma omeprazole concentrations were determined by a locally validated high performance liquid chromatography (HPLC) assay, and omeprazole pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD of Cmax, Tmax, AUC(0 --> t), AUC(0 --> infinity), and t1/2 were 0.41 +/- 0.21 and 0.48 +/- 0.27 microg/ml, 1.98 +/- 1.02 and 1.63 +/- 0.78 h, 0.95 +/- 0.78 and 1.00 +/- 0.90 microg x h/ml, 0.99 +/- 0.81 and 1.04 +/- 0.95 microg x h/ml, and 1.30 +/- 0.64 and 1.14 +/- 0.61 h for the test and reference formulations, respectively. The parametric 90% confidence intervals on mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range of 80% to 125% for AUC(0 --> t) and AUC(0 --> infinity) (88.63% to 104.98%, and 91.71% to 106.86%, respectively) but not for Cmax (76.27% to 103.63%). ANOVA revealed significant subject's effect for AUC(0 --> t), AUC(0 --> infinity), Cmax, and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 3.66, 3.92, 1.25, and 1.46, respectively. The results confirm the presence of marked individual variations in the pharmacokinetics of omeprazole and indicate that the two formulations are equivalent in relation to the extent but not the rate of absorption.     

Bioequivalence of two rimantadine tablet formulations in healthy male volunteers after single dose administration

AIM: The bioequivalence of two rimantadine tablet formulations was determined. METHODS: The study was designed as a randomized, two-period, two-sequence, crossover study. Twenty-four healthy male volunteers received a single 100 mg dose of rimantadine hydrochloride as test (Rimantadin Lachema 100 tbl. obd., produced by Lachema, a.s., Brno, Czech Republic) and reference formulations (Elumadine 100 tbl. obd., produced by Forest Pharmaceuticals, St. Louis, USA). The two administrations were separated by 14 days and were performed in the fasting state. Blood samples were obtained at 15 time points during the interval 0-120 h after administration. Rimantadine plasma concentrations were determined by gas chromatography with electron-capture detection. RESULTS: The geometric mean concentration-time profiles of rimantadine after administration of the two formulations were superimposable. The following pharmacokinetic parameters refer to the geometric mean [exp(mean +/- SD)] values for the test and reference formulations, respectively: Cmax (ng/ml) 70.5 (60.0-82.7) vs. 70.0 (59.9 to 81.7), AUC(0-infinity) (ng x h/ml) 2872 (2224 to 3707) vs. 2849 (2195-3699), AUC(0-120 h) 2744 (2184-3448) vs. 2712 (2138-3441), t(1/2) (h) 25.8 (20.1-33.0) vs. 25.7 (20.6 to 32.1). Median (range) tmax (h) values were 4.5 (2.0-8.0) and 6.0 (2.0-8.0). Parametric 90% confidence intervals for the expected mean percentage ratios (test/reference) of the pharmacokinetic variables were within the range of 97% to 105%. The median (91.1% confidence interval) difference in tmax was -0.3 h (-2.0-0.5). The point and interval estimates were identical when truncated AUCs (0-96 h, 0-72 h, 0-48 h and 0-24 h) were used in calculations. CONCLUSION: The two rimantadine formulations were equivalent in both the rate and extent ofbioavailability and they were also well tolerated. This study confirms the findings of other studies showing that for immediate release formulations of drugs with long half-lives shortening the duration over which blood samples are collected improves the economics, is more ethical and does not impair the quality of data.