Bioequivalence study of two formulations containing 400 mg dexibuprofen in healthy Indian subjects

OBJECTIVE: This study presents the results of two-period, two-treatment crossover investigations on 24 healthy Indian male subjects to assess the bioequivalence of two oral formulations containing 400 mg of dexibuprofen (CAS 51146-56-6). An attempt was also made to study the pharmacokinetics of dexibuprofen in the local population of Indian origin. METHOD: Both of the formulations were administered orally as a single dose separated by a one-week washout period. The concentration of dexibuprofen in plasma was determined by a validated HPLC method with UV detection using carbamazepine as internal standard. 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 (C(max)), and time to reach peak plasma concentration (t(max)). RESULTS: The results of this investigation indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity), and C(max) values of the two preparations. The 90% confidence interval for the ratio of the logarithmically transformed AUC(0-t), AUC(0-infinity) and C(max) were within the bioequivalence limit of 0.8-1.25 and the relative bioavailability of the test formulation was 99.04% of that of reference formulation. CONCLUSION: Thus, these findings clearly indicate that the two formulations are bioequivalent in terms of rate and extent of drug absorption. Both preparations were well tolerated with no adverse reactions observed throughout the study.     

Bioequivalence evaluation of two brands of glimepiride 4 mg tablets in healthy subjects

OBJECTIVE: This paper describes a bioequivalence study with two oral glimepiride (4 mg) tablets formulations. The reference preparation was Solosa/Aventis Pharmaceuticals Inc., USA, and the test preparation was Glimepiride/Specifar, Athens, Greece. SUBJECTS, MATERIAL AND METHODS: The study design was open, randomized, two-period, two-sequence, two-treatment with crossover involving 24 healthy male and female subjects. All subjects completed the study. Glimepiride plasma concentrations were measured utilizing a sensitive, reproducible and accurate HPLC method. Pharmacokinetic parameters used to assess bioequivalence were AUC(0_last), AUC(0-inf) for the extent of absorption and Cmax and tmax for the rate of absorption. Statistical evaluation of Cmax, AUC(0_last), and AUC(0-inf) was done after semilogarithmic transformation using a two-way analysis of variance (ANOVA). Tmax values were tested using the distribution-free Hodges-Lehman interval. RESULTS AND CONCLUSION: The parametric 90% confidence intervals for ratio T/R ranged from 90.60-108.00% (point estimate 98.90%) for AUC(0-last), 90.70-107.90% (point estimate 98.90%) for AUC(0-inf) and 86.70-103.70% (point estimate 94.80%) for Cmax, respectively. Based on the results of tmax, Kel and t(1/2), there were no statistically significant differences and the two glimepiride preparations are equivalent with respect to rate and extent of absorption as defined by the European Union bioequivalence requirements.     

Bioequivalence study of two brands of meloxicam tablets in healthy human Pakistani male subjects

Meloxicam is a cyclooxygenase-2, preferential inhibitor non-steroidal anti-inflammatory drug (NSAID) and belongs to an enolic acid (oxicam) class used for the treatment of osteoarthritis and rheumatoid arthritis. The purpose of this single dose randomized cross-over study was to assess bioequivalence of two brands of oral meloxicam tablets (Xobix manufactured by Hilton Pharma (Pvt.) Ltd. as a reference and tablet Melfax by AGP (Pvt.) Ltd. as a test) in 18 healthy male volunteers in local population of Pakistan. The data obtained were subjected to non-compartment model pharmacokinetic analysis. The value of C(max) calculated in present study was 1.051 +/- 3.762 microg/mL for reference formulation and 1.023 +/- 4.102 microg/mL (the mean +/- SEM) for test sample. The value of T(max) was 3.125 +/- 1.004 h for reference standard and 3.750 +/- 1.469 h (the mean +/- SEM) for test sample. The area under the curve from zero to infinity (AUC(0-72)) was 28.667 +/- 0.414 microg x h/mL for reference standard and 28.367 +/- 0.333 microg x h/mL for test sample (the mean +/- SEM). The t1/2 values were 13.694 +/- 0.568 h and 13.319 +/- 0.567 h (the mean +/- SEM) for reference formulation and for test sample, respectively. The test formulation was found to be bioequivalent to reference formulation based on the pharmacokinetic parameters.     

A bioequivalence study of two brands of glipizide tablets

In this open, randomized, two way crossover, bioequivalence study, two 5 mg tablet preparations of glipizide (Glipizyd tabl. 5 mg, Tarchomińskie Zak?ady Farmaceutyczne POLFA S.A., and Glibenese tabl. 5 mg, Pfizer), were compared in 24 healthy male volunteers. Pharmacokinetic variables (mean maximum plasma concentration, mean time to reach maximum plasma concentration, and the mean area under the plasma concentration-time curve) were not statistically significantly different for the two formulations. It can be concluded that the two tablet preparations of glipizide are likely to be bioequivalent.     

Pharmacokinetic and bioequivalence study of meloxicam tablets in healthy male subjects

Meloxicam (CAS 71125-38-7), a non-steroidal anti-inflammatory drug (NSAID), is used for the treatment of osteoarthritis and rheumatic arthritis. In the present study, two different oral meloxicam formulations (Melcam 15 mg tablets as test preparation and tablets of a reference preparation) were investigated in 24 healthy male subjects in order to prove bioequivalence between both preparations. A single 15 mg oral dose was administered according to an open, randomised, two-period cross-over design in the fasted state. Blood samples for the determination of meloxicam plasma concentrations were collected at pre-defined time points up to 96 h following drug administration. A wash-out period of 7-8 days separated both treatment periods. Meloxicam plasma concentrations were determined by means of a validated HPLC method with UV-detection. Maximum plasma concentrations (C(max)) of 1,146.9 ng/ml (test) and 1,064.8 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity) of 34,499.0 ng x h/ml (test) and 33,784.3 ng x h/ml (reference) were determined. The results showed nearly identical rate and extent of drug absorption. Also further pharmacokinetic parameters were well comparable. Thus, t(max) showed values of 5.00 h for both test and reference. The plasma elimination half-life (t1/2) was 18.29 h (test) und 18.94 h (reference). Both primary target parameters C(max). and AUC(0-infinity, were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 99.46%-105.24% (AUC0-infinity)) and 103.37%-112.46% (C(max)). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and C(max) the 90% confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.     

Pharmacokinetics and bioequivalence study of two brands of loxoprofen tablets in healthy volunteers

The aims of this study were to assess the pharmacokinetics and bioequivalence of two brands of loxoprofen (CAS 80832-23-6) 60 mg tablets in healthy male volunteers. The several pharmacokinetic parameters were evaluated after an oral administration after an overnight fast according to a single dose, two-sequence, and cross-over randomized design with a 1-week washout interval. Serial blood samples were collected throughout 10 h after administration of the reference and test drug. Plasma was analyzed by validated HPLC with UV detection. Several pharmacokinetic parameters, including AUC(infnity), AUC(t), C(max), T(max), T1/2, and Ke were determined from blood concentrations of both formulations. AUC(t), AUC(infinity) and C(max) were evaluated for bioequivalence after log-transformation of data using ANOVA with 90% confidence interval level. The parametric 90% confidence intervals of AUC(t), AUC(infinity), and C(max) were 90.13-106.34%, 91.43-106.94%, and 91.17-108.53%, respectively. All of the tested parameters were within the acceptable range of 80-125%. Based on these statistical considerations, it was concluded that the test drug was bioequivalent to the reference drug.     

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 study of two letrozole tablet formulations. Single dose, randomized, open-label, two-way crossover bioequivalence study of letrozole 2.5 mg tablets in healthy volunteers under fasting conditions

The study was conducted in order to compare the bioavailability of two tablet formulations containing letrozole 2.5 mg (CAS 112809-51-5). Twenty healthy subjects were enrolled in a single-centre, bioequivalence, randomised, single-dose, open-label, two-way crossover study, performed under fasting conditions with a minimum washout period of 21 days. Plasma samples were collected up to 240 h post-dosing. Letrozole levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection, LC/MS/MS method. Pharmacokinetic parameters used for bioequivalence assessment, area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(0-t)) and from time zero to infinitive (AUC(0-inf)) and maximum observed concentration (Cmax), were determined from the letrozole concentration data using non-compartmental analysis. The 90% confidence intervals obtained by analysis of variance were 90% geometric confidence Intervals of the ratio (A/B) of least-squares means from the analysis of variance (ANOVA) of the In-transformed AUC(0-t), and Cmax was within 80% to 125%. Bloequivalence between formulations was concluded both in terms of rate and extent of absorption.     

Lack of bioequivalence between two aciclovir tablets in healthy subjects

OBJECTIVE: This study aimed to compare the systemic bioavailability of two aciclovir tablets, Rouz-Aciclovir (test) and Zovirax (reference), in 12 healthy volunteers. METHODS: In a crossover design, each subject received a single oral dose of aciclovir 400 mg followed by a 7-day washout period. Plasma concentrations of aciclovir were measured for up to 12 hours using a validated high-performance liquid chromatography method with a lower limit of quantification of 50 microg/L. RESULTS: The mean values of maximum plasma concentration (C(max)), time to C(max) (t(max)), area under the plasma concentration-time curve from time 0 to 12 hours (AUC(12)) and from time 0 to infinity (AUC(infinity)), and plasma half-life following administration of the test product were 999.6 microg/L, 2.08 h, 4911.2 microg/L . h, 5417.7 microg/L . h and 3.08 h, respectively, and for the reference product 775.8 microg/L, 2.58 h, 3862.1 microg/L . h, 4295.4 microg/L . h and 3.14 h, respectively. The test/reference geometric ratio for C(max) (90% CI) was 1.30 (97.1, 174.8). The test/reference geometric ratios for AUC(12) (90% CI) and AUC(infinity) (90% CI) were 1.26 (99.7, 159.1) and 1.24 (98.9, 155.6), respectively. Therefore, the 90% CIs of C(max), AUC(12) and AUC(infinity) were not within the acceptable range of 80 and 125 suggested by the US FDA bioequivalence guideline. CONCLUSION: The results of the present study suggest that the aciclovir test product was not bioequivalent to the reference product. The exact reasons for this remain to be determined. However, we think the difference should be attributed to the difference in the type and amounts of ingredients used in the formulation that probably affect the contact time of aciclovir with the sites of absorption in the gut.     

Comparative bioequivalence study of leflunomide tablets in Indian healthy volunteers

The pharmacokinetics of teriflunomide [CAS No. 163451-81-8], the metabolite of leflunomide [CAS No. 75706-12-6] has been evaluated in adult human volunteers after oral administration of tablet formulation. However, no published data is available regarding the bioavailability of this in the Indian population. In light of the above, a study was designed to carry out a bioequivalence study of 2 preparations of leflunomide 20 mg in healthy Indian male volunteers.24 healthy male volunteers (age, 25±4.1 years; weight, 57.58±7.01 kg) were enrolled in this study. Each subject received a test and reference formulation in a single dose, fasting 2 period, 2 way crossover study with a wash out period of 4 weeks. Analysis of teriflunomide 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, AUC0-t, AUC0-∞ using GLM procedures in which sources of variation were subject, formulation, and period.The results indicated that there are no statistically significant differences between the 2 products in either the mean concentration-time profiles or in the obtained pharmacokinetic parameters. 90% confidence limits for the log transformed data of Cmax, AUC0-t, AUC0-∞. were within the acceptable range of 0.80-1.25.The results indicate that the 2 products are bioequivalent in terms of rate and extent of drug absorption. Both the preparations were well tolerated with no adverse reactions throughout the study.     

Single and multiple dose bioequivalence evaluation of two brands of gliclazide modified release tablets in healthy Chinese male volunteers

Randomized, two-way, crossover, single- and multiple-dose studies were conducted in healthy Chinese male volunteers to evaluate the bioequivalence of two brands of gliclazide (CAS 21187-98-4, 1-(3-azabicylco(3, 3, 0)oct-3-yl)-3-p-tolysulfonylurea) 30 mg tablets, viz. Gliclazide modified release (MR) tablets as test (T) and a commercial gliclazide standard preparation as reference (R) product. Each volunteer received T and R tablets separated by 7 days of a drug-free washout period. The plasma concentrations of gliclazide, determined by a validated LC-ESI-MS method, were employed to assess the pharmacokinetic parameters such as maximum and minimum observed plasma concentration (Cmax and Cmin), time to Cmax (tmax), average plasma concentration at steady state (Cav), area under plasma concentration curve (AUC(0-72), AUC(0-infinity) and AUC(ss), and degree of fluctuation for plasma concentration (DF %). As to these parameters, the analysis of variance (ANOVA) showed no significant difference and 90 % confidence intervals (CI) fell entirely into the acceptable range of bioequivalence. Based on these statistical inferences, the two formulations are considered bioequivalent in the extent and rate of absorption from both single- and multiple-dose studies.     

A randomized,crossover, assessor-blind study of the bioequivalence of a single oral dose of 200 mg of four formulations of phenytoin sodium in healthy,normal Indian volunteers

The objective of the study was to compare the bioavailability of a single oral 200-mg dose of four brands of phenytoin sodium available in the Indian market. Dilantin, Epsolin, and M-toin were compared with Eptoin, which was taken as the reference standard. A randomized, assessor-blind, four-way crossover study was done in 12 healthy Indian volunteers. The study was conducted at a clinical pharmacology ward at King Edward VII Memorial Hospital, a tertiary referral center in Mumbai (Bombay). All 12 subjects received a single oral 200-mg dose of all the formulations with a 2-week washout period between the formulations. Blood samples for plasma phenytoin levels were collected at 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours. Safety was measured by pretreatment and posttreatment biochemical investigations, physical examination, and ECG. The pharmacokinetics of the four brands of phenytoin were calculated by maximum plasma concentration (C(max)), time to reach C(max) (t(max)), area under the concentration versus time curve for time 0 to 72 hours (AUC(0-72)), and from time 0 to infinity (AUC(0- infinity)). For all brands, 90% CI of all untransformed and log transformed pharmacokinetic parameters failed to remain within prescribed limits of 80% to 120% for untransformed data and 80% to 125% for log transformed data. Since phenytoin obeys Micheles Mentens kinetics, the AUC methodology used for comparison would give only an approximate indication of relative bioavailability. M-toin was shown to be bioinequivalent to Eptoin. The other comparisons indicate but do not prove bioinequivalence of the other brands. The results of the study show that in India switching phenytoin brands could have significant implications and is not advisable once a patient is carefully titrated on one formulation.     

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.     

Pilot and pivotal study to evaluate the bioequivalence of two paroxetine 40 mg tablet formulations in healthy Chinese subjects

The purpose of this study was to conduct a pilot study in order to obtain reliable results for further planning of a well-designed pivotal trial comparing the bioequivalence (BE) of two paroxetine tablet formulations in healthy Chinese subjects. Before conducting the pivotal trial, the pilot trial enrolled 14 subjects to help in study design, establishing the recruitment period, determining pharmacokinetics (PK) time points and sample size, and assessing BE of the two formulations. The single-center, randomized, open-label, single-dose, two period crossover study with a 7-day washout interval was conducted after obtaining information from the fasted pilot trial in 72 healthy volunteers for a pivotal study under fed and fasted conditions, respectively. There were 19 PK sample collection time points employed in both the pilot and pivotal trials. A sensitive and specific liquid chromatography- tandem mass spectrometry (LC-MS/ MS) method was developed and validated for determining paroxetine in human plasma. BE between two articles was determined by calculating 90% confidence intervals (CIs) for the ratio of Cmax 91.38 - 110.39% for the pilot trial, 99.81 - 114.08% for pivotal trial under fasted condition, and 94.06 - 110.41% for pivotal trial under fed condition, AUC(0-t) 96.06 - 110.52% for pilot study, 100.88 - 113.05% for the pivotal trial under fasted condition, and 97.08 - 106.06% for pivotal study under fed condition, and AUC(0-∞) 96.17 - 110.42% for the pilot study, 100.85 - 112.81% for the pivotal trial under fasted condition and 97.22 - 106.14% for the pivotal study under fed condition, respectively. These values for the test and reference products are within the 80 - 125% interval proposed by FDA and EMEA. It was concluded that the proposed method was successfully applied to a PK study in healthy Chinese volunteers, and results showed from both the pilot and pivotal studies that the two paroxetine formulations are bioequivalent in their rates and extent of absorption.     

Comparative bioavailability/bioequivalence of two different stavudine 40 mg capsule formulations: a randomized, 2-way, crossover study in healthy volunteers under fasting condition

PURPOSE: The aim of this study was to compare the single-dose oral bioavailability of two formulations of stavudine 40 mg capsules in healthy human subjects. METHODS: A bioequivalence study of two oral capsule formulations of 40 mg stavudine was carried out in 40 healthy volunteers following a single-dose, 2-sequence, crossover and randomized design. The two formulations were stavudine 40 mg capsules (Ranbaxy Laboratories Ltd., Haryana, India) as test and zerit 40 mg capsules (Bristol-Myers Squibb, Princeton, NJ, USA) as reference product. Test and reference capsules were administered to each subject in each period separated by a 3-day washout period. Serial blood samples were collected for a period of 10 h. Blood plasma was analyzed for stavudine using a sensitive, reproducible, accurate and validated LC-MS/MS method. Pharmacokinetic parameters, including AUC(0-t), AUC(0-inf), C(max), t(max), t(1/2) and lambda(z), were determined from plasma concentrations for both formulations. AUC(0-t), AUC(0-inf) and C(max) were tested for bioequivalence after log-transformation of data. RESULTS: The LC-MS/MS method, used to quantify stavudine in human plasma, was specific and sensitive for stavudine. Plasma concentration profiles of stavudine test and reference treatments were similar. Geometric mean ratios and 90% confidence intervals for C(max), AUC(0-t) and AUC(0-inf) for stavudine were 99.9 (93.9-106), 99.9 (98.4-101) and 99.8 (98.2-101), respectively. Untransformed results for the same parameters were consistent with the natural log-transformed data. CONCLUSION: The two stavudine 40 mg capsule formulations examined were bioequivalent and may be used interchangeably in medical practice.     

A single-dose, two-way crossover, bioequivalence study of dexmethylphenidate HCl with and without food in healthy subjects

Attention deficit hyperactivity disorder (ADHD) in children is effectively treated by racemic oral methylphenidate (dl-MPH). The d-isomer (d-MPH) has been developed as an improved treatment for ADHD since only half the racemic dose is used. This study, performed in healthy subjects, assessed the effect of food on the pharmacokinetics of dexmethylphenidate hydrochloride (d-MPH HCl) in a single dose (2 x 10-mg tablets), two-way crossover with d-MPH administered to subjects in both a fasting state or after a high-fat breakfast. There were no serious or unexpected adverse events during the course of this study, with most events reported in comparable numbers of fed and fasted subjects. The bioequivalence of d-MPH was similar with or without food, with 90% confidence intervals of 88.2% to 104.6% and 105.9% to 118.2% for ln(C(max)) and ln[(AUC(0-infinity))], respectively. There was a marginal but statistically significant 1-hour increase in t(max) in the fed versus fasted state, reflecting an absorption delay. The rate of formation of the major metabolite, d-ritalinic acid (d-RA), was marginally decreased ( approximately 14%) after food. The extent of exposure to d-RA was similar (within 1.2%) between both treatments. There was a marginal but statistically significant difference in mean t(max) for d-RA between fed and fasted conditions, with peak concentration occurring 1.5 hours later after d-MPH administration with food. There was no measurable in vivo chiral inversion of d-MPH to l-MPH in plasma. In addition, the metabolism of d-MPH was stereospecific as d-MPH only produced d-RA. In summary, food had no substantial effect on the bioavailability of d-MPH, with an equivalent rate and extent of exposure obtained. Therefore, d-MPH can be administered without regard to food intake.     

Pharmacokinetics and bioequivalence study of doxycycline capsules in healthy male subjects

The aim of the present study was to compare the bioavailability of doxycycline (CAS 564-25-0) from two different doxycycline hyclate (CAS 24390-14-5) capsules (Monodoks 100 mg capsule as test preparation and 100 mg capsule of the originator product as reference preparation) in 24 healthy male subjects. The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 16 days. Blood samples for pharmacokinetic profiling were taken up to 72 h post-dose, and doxycycline plasma concentrations were determined with a validated HPLC method with UV-detection. Maximum plasma concentrations (Cmax) of 1,715.1 ng/ml (test) and 1,613.3 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 28,586.5 ng x h/ml (test) and 29,047.5 ng x h/ml (reference) were calculated. The median tmax was 1.88 h (test) and 2.00 h (reference). Plasma elimination half-lives (t1/2) of 16.49 h (test) and 16.75 h (reference) were determined. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA) and the 92.39 %-103.53% (AUC(0-infinity)) and 98.45%-111.74% (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 0%-125%.