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

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

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

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

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

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

Comparative bioavailability study of 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.     

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 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.     

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.     

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 two sertraline tablet formulations after single-dose administration in healthy Thai volunteers

OBJECTIVE: To compare the bioavailability of two sertraline tablet (50 mg) formulations (Serlift from Ranbaxy Laboratories Ltd., Gurgaon Haryana, India, as a test formulation and Zoloft from Pfizer Australia Pty Ltd., West Ryde, New South Wales, Australia, as a reference formulation) in 24 healthy Thai male volunteers under fasting condition. MATERIALS AND METHODS: A randomized, 2-treatment, 2-period, 2-sequence, single-dose, crossover study with a washout period of 3 weeks, was conducted in 24 healthy Thai male volunteers. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours following drug administration. Plasma concentrations of sertraline were determined using validated LC-MS/MS method. Noncompartmental pharmacokinetics and statistical analyses were performed using SAS software for Windows, release 9.1 (SAS Institute Inc., Cary, NC, USA). RESULTS: The ratio of least square means and the 90% confidence intervals (CI) of the log-transformed data were 0.9950 (0.9111-1.0866) for Cmax, 1.0153 (0.9576-1.0764) for AUC(0-t) and 1.0110 (0.9510-1.0747) for AUC(0-infinity). In addition, the median tmax values for the test and reference formulations were similar (5.00 h). The 90% CI for Cmax, AUC(0-t) and AUC(0-infinity) were within the 0.8-1.25 interval of the US-FDA. CONCLUSIONS: The test formulation (Serlift, Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India) is bioequivalent to the reference formulation (Zoloft, Pfizer Australia Pty Ltd., West Ryde, New South Wales, Australia) both in terms of rate and extent of absorption after single-dose administration under fasting condition.     

Nevirapine/lamivudine/stavudine as a combined-formulation tablet: bioequivalence study compared with each component administered concurrently under fasting condition

OBJECTIVE: The objective of the study was to compare the bioequivalence of a fixed-dose combination of a nevirapine 200 mg, lamivudine 150 mg and stavudine 30 mg combination tablet with application of the 3 medications, at the same dosage, concurrently as separate formulations, in healthy, adult subjects under fasting conditions. MATERIAL AND METHODS: An open-label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single-dose, crossover bioavailability study was conducted in 40 subjects with 21-day washout period between each treatment. Blood samples were collected for 168 hours. Plasma concentrations of nevirapine, lamivudine and stavudine were determined using a validated LC-MS-MS method. Noncompartmental pharmacokinetics and statistical analyses were performed using SAS (SAS Institute Inc., Cary, NC, USA) software (SAS System under Windows, Version 8.02). RESULTS: The ratios of least-square means and the 90% confidence intervals of the log-transformed data were calculated for AUC(0-t), AUC(0-inf), and Cmax. The 90% confidence interval for least-square mean ratio between test and reference formulation for log-transformed parameters Cmax, AUC(0-t) and AUC(0-inf) were within the requirements of the 80-125% range. CONCLUSION: The test formulation (Ranbaxy Laboratories Ltd., Gurgaon, India) is bioequivalent to the reference formulations both in terms of rate and extent of absorption after single-dose administration under fasting condition.     

Bioequivalence studies of 2 oral cefaclor capsule formulations in chinese healthy subjects

An open-label, single-dose, randomized, crossover study was carried out in 20 Chinese healthy male subjects to compare the pharmacokinetics of 2 cefaclor (CAS 53994-73-3) formulations after administration of a single 250 mg dose of each drug with a 1-week wash-out period. Blood samples were collected before and with 6 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detector. 2 formulations were evaluated using the following pharmacokinetic parameters: AUC0-t, Cmax and tmax was analyzed nonparametrically. The 90% confidence interval (CI) of the ratios (teat/reference) of log-transformed AUC0-t and Cmax fell within the bioequivalence acceptance range of 80-125%. The results showed that the 90% CI of the ratios of AUC0-t and Cmax were 105.1% (101.0-109.4%) and 92.4% (82.5-103.4%), respectively, which therefore could conclude 2 oral cefaclor capsule formulations of cefaclor are bioequivalent. Both treatments showed similar tolerability and safety.     

Comparative bioavailability of two different diclofenac formulations in healthy volunteers

The aim of the study was to assess the bioequivalence of two different diclofenac (CAS 15307-86-5) formulations (diclofenac free acid suspension as test formulation and diclofenac resinate suspension, Cataflam, as reference formulation) in 24 healthy volunteers. After an overnight fast, the volunteers received a single oral dose (50 mg) of each formulation, following an open, randomized, two-period crossover design, with a fourteen-day washout interval between doses. Serum samples were obtained over a 24-h interval post-dosing, and were analysed for their diclofenac content by HPLC-UV. No adverse effect was reported for any of the formulations administered. Geometric mean test/reference individual ratios were: 92.8% for AUC(0-24 h), 93.2% for AUC(0-infinity), 117.2% for Cmax, 131.0% for Ke and 76.2% for T1/2. The variability of Cmax parameter expressed as CV was greater than 25%. Since the 90% CI for AUC(0-24 h) mean ratio were within the 80-125% interval proposed by the Food and Drug Administration, it can be concluded that diclofenac free acid formulation is bioequivalent to diclofenac resinate formulation for the extent of absorption. Since the European Community Agency accepts a 90% CI for Cmax of 70-143%, it can be concluded that diclofenac free acid formulation is bioequivalent to diclofenac resinate formulation for both the rate and the extent of absorption after single dose administration.     

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.     

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 of two fluconazole capsule formulations in healthy volunteers

This work reports the bioavailability of two fluconazole (CAS 86386-73-4) capsule formulations in 24 healthy volunteers of both sexes who received a single oral dose (150 mg). The study was conducted using an open, randomized, two-period crossover design with two-week washout interval. Plasma samples were obtained up to 168 h after drug administration and fluconazole concentration were analyzed using electrospray tandem mass spectrometry coupled to liquid chromatography. The pharmacokinetic parameters obtained for fluconazole after the administration of each formulation included the area under the curve (AUC)(0-168 h), AUC(0-infinity), maximum concentration (Cmax), time to reach Cmax (Tmax), elimination constant (Ke) and half-life (T1/2). The 90% confidence interval for the geometric mean of the individual ratio test formulation/reference formulation were 97.18-108.60% for AUC0-168 h), 90.87-111.11% for AUC(0-infinity), 104.88-114.88% for Cmax 90.38-136.79% for Ke, 91.87-108.93% for T1/2 and (-)1.5-(-)0.10 for Tmax (for individual differences). Since for both Cmax or AUC the 90% CI are within the interval proposed by the Food and Drug Administration (FDA), the test formulation (Zoltrix) is bioequivalent to the reference formulation for both the rate and the extent of absorption after single dose administration.     

Comparison of two microemulsion of cyclosporine A in healthy volunteers

This study evaluated the bioequivalence of a new Cyclosporine A microemulsion formulation in comparison to the reference market standard. Twenty-four adult healthy volunteers were randomised to receive the two Cyclosporin A microemulsion formulations, at a dose of 2.5 mg/kg, according to a cross-over design. Blood samples were taken before drug administration and at 12 points within 24 hours. Cyclosporine A whole blood concentrations were determined by HPLC. The pharmacokinetic parameters AUC0-t and AUC0-infinity were calculated by the trapezoidal rule, Cmax and Tmax were obtained directly from blood data. AUCs and Cmax were tested for bioequivalence after log transformation of data, differences for Tmax were evaluated by the rank test of Wilcoxon for paired data. The 90% confidence interval ratio between tested/reference drug was 0.98 for AUC0-t, 0.96 for AUC0-infinity and 1.01 for Cmax. All of them were within the range of bioequivalence. Tmax was 1.60 +/- 0.44 hours after test drug and 1.67 +/- 0.48 after reference drug (p = 0.27, Wilcoxon test). According to these results the two Cyclosporine A microemulsion formulations can be considered bioequivalent.     

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.     

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 study of a fixed dose combination of nitazoxanide and ofloxacin in Indian healthy volunteers

OBJECTIVE: The pharmacokinetics of nitazoxanide (CAS 55981-09-4) and ofloxacin (CAS 82419-36-1) has been extensively evaluated in adult human volunteers individually after oral administration of tablet formulation. However, no published data is available regarding the combined pharmacokinetics and bioavailability of this particular fixed dose combination. In light of the above, a clinical study was designed to evaluate the bioequivalence of two fixed dose combination (FDC) products of two manufacturers containing nitazoxanide 500 mg and ofloxacin 200 mg in healthy Indian male volunteers. METHODS: 24 healthy male volunteers (age 25 +/- 4.6 years; weight 74.5 +/- 7.87 kg) were enrolled in this study. Each subject received a Test fixed dose combination and a Reference fixed dose combination formulation in a randomized, single dose, fasting state, two period, crossover study design with a 1-week washout period between the doses. Extraction of the drugs from the plasma was carried out by precipitation method. Analysis of tizoxanide (active metabolite of nitazoxanide) and ofloxacin from plasma samples was done by a simple and sensitive HPLC method using UV detection developed in our laboratory. An analysis of variance was performed on the pharmacokinetic parameters Cmax, AUC(0-t), AUC(0-infinity). using general linear model (GLM) procedures in which sources of variation were subject, formulation, period. RESULTS: The results of this investigation indicated that there were no statistically significant differences between the two products in either the mean concentration-time profiles or in the obtained pharmacokinetic parameters. 90 % confidence limits for the log-transformed data of Cmax, AUC(0-t), AUC(0-infinity) were within the acceptable range of 0.80-1.25. CONCLUSION: Thus, these findings clearly indicate that the two products are bioequivalent in terms of rate and extent of drug absorption. Both the preparations were well tolerated with no adverse reactions seen throughout the study.     

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

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