Bioequivalence assessment of Lovrak (Julphar, UAE) compared with Zovirax (Glaxo Wellcome, UK)--Two brands of Acyclovir--in healthy human volunteers

Two studies were performed to assess the relative bioavailability of Lovrak (Julphar, UAE) compared with Zovirax (Glaxo Wellcome, UK) at the International Pharmaceutical Research Center (IPRC), Amman, Jordan. One study involved acyclovir tablets and the other acyclovir suspension. Each study enrolled 24 volunteers and in both studies, after an overnight fasting, the two brands of acyclovir were administered as a single dose on 2 treatment days separated by 1 week washout period. After dosing, serial blood samples were collected for a period of 16 h. Plasma harvested from blood, was analysed for acyclovir by an HPLC method with UV detection. Various pharmacokinetic parameters including AUC0-t, AUC0-infinity, Cmax, Tmax, T1/2 and Kelm were determined from plasma concentrations for both formulations and found to be in good agreement with the reported values. AUC0-t, AUC(0-proportional to), and Cmax were tested for bioequivalence after log-transformation of data. No significant difference was found based on ANOVA; 90% confidence intervals for the test/reference ratio of these parameters were found within the bioequivalence acceptance range 80%-125%. Based on these statistical inferences it was concluded that a Lovrak tablet is bioequivalent to a Zovirax tablet and that Lovrak suspension is bioequivalent to Zovirax suspension.     

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.     

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.     

阿昔洛韦片体内生物利用度研究

研究两种阿昔洛韦片药物动力学及生物等效性。采用反相高效液相色谱法 ( C18柱 ,流动相为 0 .1%醋酸溶液 ,流速 1.4 ml/min,测定波长 2 54nm)测定 10名志愿受试者单剂量口服 60 0 mg阿昔洛韦片后 ,阿昔洛韦血药浓度变化情况。结果表明供试品和参比制剂为生物等效制剂。药时曲线下面积分别是 :5.30± 1.19(μg· h) /ml与 5.4 1± 1.34 ( μg· h) /ml,达峰时间分别为 :1.84± 0 .55h与 1.97± 0 .39h,峰浓度分别是 :1.0 9± 0 .18μg/ml与 1.0 6± 0 .2 2 μg/ml。     

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.     

Relative bioavailability of three cefixime formulations

Three galenic formulations of cefixime (tablet, syrup and dry suspension) containing 200 mg each were compared with respect to their relative bioavailability in twelve healthy volunteers. All three formulations showed reliable absorption. Mean peak plasma concentrations were reached after 3.3-3.5 h, mean terminal half lives were 2.9-3.1 h. 18-24% of the dose administered were recovered unchanged in the urine. Best bioavailability was obtained with the dry suspension (AUC0-infinity = 25.8 +/- 7.0 micrograms/ml h; Cmax = 3.4 +/- 0.9 microgram/ml), followed by the tablet (AUC0-infinity = 20.9 +/- 8.1 micrograms/ml h; Cmax = 3.0 +/- 1.0 micrograms/ml) and the syrup which is based on triglycerides (AUC0-infinity = 17.8 +/- 5.9 micrograms/ml h; Cmax = 2.4 +/- 0.7 micrograms/ml). The statistical analysis resulted in bioinequivalence between dry suspension and syrup. It is concluded that best bioavailability of cefixime after oral administration is guaranteed when taken in an "aqueous medium" either as dry suspension or as tablet with "plenty of liquid".     

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.     

国产与进口美洛昔康片单次给药后人体药动学(英文)

目的 :比较健康志愿者国产与进口美洛昔康片的人体药动学和相对生物利用度。方法 :采用单次给药 2周期交叉设计 ,HPLC法测定 12名健康男性志愿者口服 15mg美洛昔康后血药浓度 ,计算药动学参数和国产片的相对生物利用度。结果 :2种制剂的药时曲线符合一级吸收的一室开放模型。国产与进口片的药动学参数分别是AUC0 - 96 为 (6 7±s 14 )mg·h·L- 1和 (6 4± 15 )mg·h·L- 1;AUC0 -∞ 为 (73± 19)mg·h·L- 1和 (70± 18)mg·h·L- 1;Cmax为 (2 .3± 0 .5 )mg·L- 1和 (1.6± 0 .3)mg·L- 1;Tmax为 (2 .0± 1.6 )h和 (6± 3)h ;T12 ke为 (2 5± 6 )h和 (2 4± 5 )h ;MRT为 (4 0± 13)hand (39±8)h。方差分析表明两者AUC之间无显著差异 (P>0 .0 5 ) ,但两者的Cmax和Tmax之间有显著差异 (P<0 .0 5 )。结论 :国产片的释药速率比进口片快 ,其相对生物利用度为 (10 5± 13) %。     

Pharmacokinetics and bioequivalence study of ranitidine film tablets in healthy male subjects

The aim of the present study was to compare the bioavailability of ranitidine (CAS 66357-35-5) from two different ranitidine hydrochloride (CAS 66357-59-3) film tablets (Ranitab 150 mg film tablets as test preparation and 150 mg film tablets of the originator product as reference preparation). The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 9 days. Blood samples for pharmacokinetic profiling were taken up to 24 h post-dose, and ranitidine plasma concentrations were determined with a validated HPLC method with UV-detection. Maximum plasma concentrations (Cmax) of 461.8 ng/ml (test) and 450.6 ng/ ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC (0-infinity) of 2,488.6 ng . h/ml (test) and 2,528.8 ng . h/ml (reference) were calculated. The median tmax was 2.83 h (test) and 3.04 h (reference). Plasma elimination half-lives (t1/2) of 2.78 h (test) and 2.89 h (reference) were determined. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 91.93 %-106.98 % (AUC (0-infinity) and 92.34%-118.85% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90 % confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80 %-125 %.     

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.     

Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist

The purpose of the study was to investigate the effect of food intake on the pharmacokinetics and metabolism as well as the relative bioavailability of bosentan. Sixteen healthy male subjects were treated in a randomized, four-way, crossover design with single oral doses of 125 mg bosentan, given as one tablet (with or without food), two tablets of 62.5 mg (with food), and a suspension (without food). The pharmacokinetic parameters of bosentan (and also three of its metabolites) were very similar after the four treatments: geometric means for Cmax and AUC0-infinity, ranged from 1.3 to 1.6 microg/ml and from 7.8 to 8.9 microg x h/ml, respectively, and median t(max) from 3.0 to 4.0 hours. The bioavailability of the 125 mg tablet relative to that of the suspension, both given fasted, was 102%. In the presence of food, Cmax and AUC0-max increased by 22% and 10%, respectively, whereas the two 62.5 mg tablets were bioequivalent to the 125mg tablet, both under fed conditions. The pharmacokinetics of the metabolites was independent of the treatment administered. In conclusion, bosentan bioavailability from the newly developed 125 mg tablet formulation is similar to that of the suspension, and food intake does not influence its pharmacokinetics to a clinically relevant extent.     

A randomized, crossover study to determine bioequivalence of two brands of dexibuprofen 400 mg tablets in healthy Asian adult male subjects of Indian origin

AIM: To estimate the bioavailability and evaluate bioequivalence of a single dose of a dexibuprofen tablet (test formulation, containing dexibuprofen 400 mg, manufactured by Emcure Pharmaceuticals Ltd., Pune, India) and to compare it with that of a single dose of a Seractil tablet (reference formulation, containing dexibuprofen 400 mg, manufactured by Genus Pharmaceuticals, Bershire, UK) under fasting conditions. SUBJECTS AND METHODS: Using a two-treatment, two-period, two-sequence, randomized crossover design, test and reference formulations were administered as individual single doses to 24 healthy adult Asian male subjects of Indian origin under non-fed conditions, with 4 days washout period between dosing. 17 blood samples were drawn from each subject over a 12-hour period. Pharmacokinetic parameters, Cmax, AUC0-t, AUC0-infinity and Cmax/AUC0-infinity were calculated from the plasma concentration-time data of each individual and during each period by applying non-compartmental analysis. Analysis of variance was carried out using logarithmically transformed and non-transformed values of the stated pharmacokinetic parameters. Data for test and reference formulations were analyzed statistically to test for bioequivalence of the two formulations. RESULTS: All 24 subjects who received the two formulations on two occasions with a washout period of 4 days, completed the study and provided an adequate amount of blood at each sampling point. After oral administration the values of Cmax (microg/ml), tmax (h), AUC0-t (microg/ml x h), AUC0-infinity (microg/ml x h) for reference and test formulations were 23.501 and 22.948, 1.156 and 1.281, 69.795 and 68.455, and 72.454 and 70.208, respectively. ANOVA and CI test showed no significant (p > 0.05) variation in these pharmacokinetic parameters of test and reference formulations. When the AUC0-t values for both formulations for non-transformed and log-transformed data were compared, the test formulation showed a bioavailability of 98.08% and 99.56%, respectively, as compared to reference formulation. These values are within the acceptance limit of 80 - 120%. No adverse events were observed in any of the subjects during the two runs of the study. Both clinical and laboratory parameters of all subjects showed no clinically significant changes. CONCLUSION: The test formulation containing dexibuprofen 400 mg (manufactured by Emcure Pharmaceuticals Ltd., Pune, India) was bioequivalent to reference formulation (Seractil, manufactured by Genus Pharmaceuticals, Berkshire, UK). Both formulations were well tolerated. The test formulation can be considered a pharmaceutically and therapeutically equivalent alternative to Seractil.     

Comparative bioavailability study of two cefixime formulations administered orally in healthy male volunteers

The bioavailability of a new cefixime ((6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino) acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylic acid, CAS 79350-37-1) tablet preparation (Loprax) was compared with that of a reference preparation of the drug in 24 healthy male volunteers. The trial was designed as an open, randomized, single-blind, two-sequence, two-period crossover study. Under fasting conditions, each subject received a single oral dose of 400 mg cefixime tablet as a test or reference formulation on 2 treatment days. The treatment periods were separated by a one-week washout period. The plasma concentrations of the drug were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-24h, AUC0-infinity, Cmax, t1/2, and Ke. The mean AUC0-infinity of cefixime was 45008.7 +/- 10989.9 and 45221.3 +/- 2155.7 n x h/ml for the test and reference formulation, respectively. The maximum plasma concentration (Cmax) of cefixime was on average 4746.9 +/- 1284 ng/ml for the test and 4726.3 +/- 1206.9 ng/ml for the reference product. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for test and reference tablets. The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of Cmax, AUC0-infinity and AUC0-24h of cefixime were in the bioequivalence range (94%-112%). Therefore, the two formulations were considered to be bioequivalent.     

Pharmacokinetics and relative bioavailability of prajmalium bitartrate after single oral dosing.

Pharmacokinetics and relative bioavailability of the marketed prajmalium bitartrate tablet (Neo-Gilurytmal, CAS 2589-47-1) compared to an oral solution were investigated in an open, randomized, single-dose two-fold crossover study in 20 healthy male volunteers. One subject was identified to be a poor metabolizer. In the study population with normal metabolic status the two oral formulations proved to be bioequivalent with regard to the pharmacokinetic parameters Cmax, AUC(0-Tlast), AUC(0-infinity) and Ae(24h). tmax was prolonged after administration of the tablets. The relative bioavailability of prajmalium bitartrate from the tablet amounted to 112%. The poor metabolizer demonstrated in both oral formulations high plasma concentrations, increased AUCs and prolonged terminal half-lives as well as increased renal excretion of prajmalium bitartrate.     

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.     

Systemic bioavailability of nasally applied chlorphenamine maleate (0.4% nasal spray) relative to tablets administered perorally

AIM: This study investigated the bioavailability of single doses of 1.12 and 2.24 mg chlorphenamine maleate applied intranasally (0.4% nasal spray) relative to a single peroral dose of 8 mg chlorphenamine maleate (tablets). METHODS: Twenty-four (24) subjects were treated with single nasal doses of 1.12 mg and 2.24 mg chlorphenamine maleate (0.4% nasal spray) and two 4 mg chlorphenamine maleate tablets (Piriton) on 3 separate study days according to a 3-way cross-over design with a 7-day wash-out between periods. Blood was sampled before and at 0.25, 0.50, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12, 16 and 24 hours after drug administration. Additional blood samples were obtained 36, 48 and 72 hours after peroral administration only. All subjects were included in the pharmacokinetic analysis. RESULTS: Nasally applied chlorphenamine maleate was readily absorbed, reaching peak plasma levels after 0.25 to 3.0 hours. The dose-normalized estimated mean Cmax values were 1.24, 1.43 and 1.21 ng/ml for the peroral tablet and the 1.12 mg and 2.24 mg nasal dose, respectively. The dose-normalized estimated mean AUC(0-infinity) values were 25.91, 26.44 and 25.56 ng x h/ml for the tablet and the 1.12 and 2.24 mg nasal dose, respectively. The estimated treatment ratios (nasal dose to tablet) of the dose-normalized values for the 1.12 mg nasal dose were 1.15 (900 CI: 1.0-1.32) and 1.02 (90% CI: 0.88-1.18) for Cmax and AUC(0-infinity), respectively, for the 2.24 mg nasal dose they were 0.98 (90% CI: 0.85-1.13) and 0.99 (90% CI: 0.85-1.13) for Cmax and AUC(0-infinity), respectively. The other pharmacokinetic characteristics (tmax, t(1/2), lambda(z), AUC(0-tf), MRTtot, CL/f and Vz/f) were comparable across all treatments. These data indicate that the disposition of chlorphenamine maleate was independent of the route and dose of administration. CONCLUSIONS: Chlorphenamine maleate is readily absorbed after nasal application using a 0.4% nasal spray. The nasal administration showed that the systemic bioavailability at the two dose levels used was comparable to that for the tablet. Maximum concentrations on the low dose, however, were higher and those on the high dose were comparable to those for the tablet. The nasal application of chlorphenamine maleate does not alter the overall systemic exposure compared to the oral route.     

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.     

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.     

Comparative pharmacokinetic and relative bioavailability study of coated and uncoated azithromycin powder for suspension in healthy Bangladeshi male volunteers

Azithromycin (AZT; CAS 83905-01-5) is an efficient antibiotic and is widely prescribed in Bangladesh. The taste of uncoated AZT suspension is bitter. Although several taste masked oral suspensions of AZT are available in Bangladesh, information regarding the bioavailability of these formulations in Bangladeshi population is unavailable. The purpose of this study was to compare the relative bioavailability and other pharmacokinetic properties of two oral formulation of AZT (200 mg/5 ml) suspensions, the uncoated reference product and coated test product (Tridosil 200 mg/5 ml) and to evaluate whether these formulations meet the FDA criteria to assume bioequivalence in Bangladeshi male volunteers. A randomized, single-dose, two-way cross-over, open-label pharmacokinetic study was conducted in 24 healthy male volunteers after administration of a single dose of 500 mg AZT suspension under fasting condition following a washout period of three weeks. Blood samples were collected in different time intervals and analyzed for serum AZT concentration using a validated LC/MS/MS method. The pharmacokinetic parameters were determined by the non-compartmental method. From serum data, the obtained values for test and reference products were 383.21 +/- 11.59 and 432.28 +/- 7.22 ng/ ml for Cmax; 5677.47 +/- 1229.53 and 6144.56 +/- 1098.70 h x ng/ml for AUC(0-120); and 6085.29 +/- 1267.53 and 6694.15 +/- 1222.50 h x ng/ml for AUC(0-infinity), respectively. On analysis of variance, no period or sequence effects were observed for any pharmacokinetic property; however, a significant formulation effect was observed for Cmax and AUMC(0-infinity). The 90% confidence intervals of the test formulation/reference mean ratios of the Intransformed Cmax, AUC(0-120) and AUC(0-infinity) mean values were found to be 87.89% to 89.36%, 87.96% to 95.71% and 86.77% to 94.29% respectively. In this single-dose study of AZT, it was found that the test formulation met the regulatory criteria for bioequivalence to the reference suspension formulation.     

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%.