Prediction of steady state bioequivalence relationships using single dose data II-nonlinear kinetics

Two nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmax and area under the plasma-concentration time curve values from 0 to infinity (AUC 0-infinity) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing. The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC 0-infinity showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmax which showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmax and AUC 0-infinity from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmax confidence intervals following single and multiple dosing was at variance with the experimental data for formulations A and B.     

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

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

Comparative bioavailability study of cefixime (equivalent to 100 mg/5 ml) suspension (Winex vs Suprax) in healthy male volunteers

This investigation was carried out to evaluate the bioavailability of a new suspension formulation of cefixime (100 mg/5 ml), Winex, relative to the reference product, Suprax (100 mg/5 ml) suspension. The bio-availability study was carried out in 24 healthy male volunteers who received a single oral dose (200 mg) of the test (A) and the reference (B) products on 2 treatment days after an overnight fast of at least 10 hours. The treatment periods were separated by a one-week washout period. A randomized, balanced two-way crossover design was used. After dosing, serial blood samples were collected over a period of 16 hours. Plasma concentrations of cefixime were analyzed using a sensitive high-performance liquid chromatographic assay. The pharmacokinetic parameters for cefixime were determined using standard non-compartmental method. The parameters AUC(0-t), AUC(0-infinity), Cmax, Kel, t1/2 and Cmax/AUC(0-infinity) were analyzed statistically using raw and log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pnfinity harmacokinetic parameters: AUC(0-t), AUC(0-infinity) Cmax, and Cmax/AUC(0-infinity) were within the range 80 - 125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax, and Cmax/AUC(0-infinity) were 88.93 - 107.10%, 89.09 - 107.11%, 89.63 - 108.58% and 96.85 - 105.29%, respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC(0-t), AUC(0-infinity), and Cmax using the Schuirmann's two one-sided t-tests. Therefore, the two formulations were considered to be bioequivalent.     

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.     

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.     

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 study of two preparations of letrozole in healthy subjects

The bioavailability of a new letrozole (CAS 112809-51-5) preparation was compared with the reference preparation of the drug in 25 healthy volunteers, aged between 18 and 33. A single dose of 2.5 mg was given orally in the fasted state, using a randomized two-way, cross-over protocol. A washout period of two weeks separated both treatment periods. Blood samples were obtained at regular time intervals, until 312 h after drug administration. After solid phase extraction (SPE) letrozole plasma levels were measured by high pressure liquid chromatography that was validated before the start of the study (UV detector, fluoroletrozole as an internal standard). The limit of quantification was 1.4 nmol/ml. The following pharmacokinetics parameters were calculated from letrozole plasma concentrations: AUC(0-infinity), AUC(0-t), Cmax, tmax, F(rel), MRT, t(1/2), k(el). The confidence intervals for the statistical calculations of AUC(0-infinity), Cmax, tmax were 95 % and AUC(0-t), MRT, t(1/2), k(el) were tested by means of the unpaired t-tests procedure and after logarithmic transformation for overall significant differences using analysis of variance--three-way ANOVA. The AUC(0-infinity) ratio test/reference and the 90 % confidence interval were 99.52 %, and 94.05-107.31%, respectively. The Cmax ratio test/reference and the 90 % confidence interval were 89.18 %, and 84.48-98.60%, respectively. AUC(0-infinity) and Cmax ratios (90 % CI) were within the 80-125 % interval required for bioequivalence as stipulated in the current international regulations of the European Agency for the Evalution of Medicinal Products and the Food and Drug Administration. Therefore it is concluded that the new letrozole preparation is therapeutically equivalent to the reference preparation for both the extent and the rate of absorption after single dose administration in healthy volunteers.     

Bioequivalence assessment of two different tablet formulations of diltiazem after single and repeated doses in healthy subjects

The study was performed on 14 healthy volunteers in order to compare the pharmacokinetics and hence assess the bioequivalence of two different tablet formulations of diltiazem administered orally. The study was carried out after single doses (60 mg) and repeated doses (60 mg three times a day for six days and 60 mg on the seventh day) according to a randomised, cross-over, open design. The pharmacokinetic parameters AUC0-infinity (ng h/ml), Tmax(h) and Cmax (ng/ml) were calculated for the two formulations after a single dose, while AUCt1-t2 (= AUC for a repetitive dose interval or dosing cycle, ng h/ml) and PTF (peak trough fluctuation) were calculated after repeated doses. The bioequivalence assessment was the shortest 90% confidence interval for the ratio (difference) of expected medians in the respective bioequivalence range (0.80-1.20). The results of this study show that, after either a single dose or repeated doses of test or reference formulations of diltiazem, the pharmacokinetics of the two formulations are similar. The ratios of AUC on day 1 (for single-dose treatment) and on day 7 (for repeated-dose treatment), and the corresponding 90% confidence intervals demonstrate bioequivalence between the two formulations of diltiazem within the accepted range of 0.80-1.20 (80-120%).     

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 of two oral ciprofloxacin tablets formulations

The relative bioavailability of a new 750 mg tablet formulation of ciprofloxacin (test formulation supplied by Dr. August Wolff GmbH and Co., Germany) was compared with that of Ciprobay tablets 750 mg (reference formulation from Bayer Vital GmbH and Co., Germany). Twenty-four healthy volunteers (12 male and 12 female) were included in this single-dose, 2-sequence, crossover randomized study. Blood samples were obtained prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24 and 30 hours after drug administration. Plasma concentrations of ciprofloxacin were determined by HPLC. No differences were found when the in vitro dissolution profiles of both formulations were compared. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were tested for bioequivalence after log-transformation of data, and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following mean values for the test/reference ratios (90% standard confidence intervals in parenthesis (ln-transformed data): 1.01 (0.95-1.07) for AUC(0-t), 0.99 (0.93-1.05) for AUC(0-infinity), 1.05 (0.97-1.14) for Cmax and 1.06 (0.97-1.15) for Cmax/AUC(0-infinity). The nonparametric confidence interval for tmax was 0.77-1.15. All parameters showed bioequivalence between both formulations as their confidence intervals were within the bioequivalence acceptable range of 0.80-1.25 limits; the 90% confidence interval for tmax slightly exceeded limits of bioequivalence. We conclude that both formulations show bioequivalence for both the rate and the extent of absorption.     

In vivo bioequivalence study of Sulpirid (GYKI-Alkaloida) and Dogmatil fort (Delagrange) 200 mg sulpiride tablets in healthy volunteers]

A single-dose, "crossover" bioequivalence study was conducted in healthy volunteers by comparing sulpiride serum levels after oral administration of the Test Product Sulpiride (200 mg) (GYKI-Alkaloida) in fasting subjects with those produced after oral administration of a marketed reference product (200 mg) (Delagrange Co., France). Statistical comparisons of Cmax, Tmax and AUC0-infinity have been performed utilizing ANOVA with subject, group, subject within group, period and product as sources of variance. No significant differences between the Test Drug and the Reference Drug considering the pharmacokinetic parameters Cmax, Tmax and AUC0-infinity were found. The 95% confidence intervals were as follows: AUC0-infinity: -20.46% and 31.19%, Cmax: -28.05% and 26.65% and Tmax: -43.53% and 20.67%. In the study for the analysis of Sulpiride a specific HPLC procedure with uv detection (lambda = 228 nm) and an internal standard were applied according to P. Nicolas et al. with modification. Sulpiride levels in serum reached a maximum at 4.4 hr +/- 1.5 (S.D.) following administration of Sulpiride tablet and at 5.0 hr +/- 0.8 (S.D.) after Dogmatil fort tablet. The maximal serum concentrations were 506.1 ng/ml +/- 87.2 (S.D.) and 509.1 ng/ml +/- 101.9 (S.D.) for Sulpiride and Dogmatil fort, respectively. The half-life of Sulpiride in serum was 9.9 hr +/- 1.3 (S.D.) following dosing with Dogmatil fort tablet and 12.2 hr +/- 3.0 (S.D.) following dosing with Sulpiride tablet.     

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 bioequivalence study of two isotretinoin soft gel capsule formulations in healthy male volunteers

OBJECTIVE: To assess the bioequivalence of 2 oral isotretinoin (20 mg) soft gel capsule formulations. The reference preparation was Roaccutan/Roche while the test preparation was A-Cnotren/Pharmaten, Athens, Greece. SUBJECTS, MATERIAL AND METHODS: The study was an open, randomized, 2-period, 2-sequence, 2-treatment crossover, involving 38 healthy male volunteer subjects. All volunteers completed the study. Isotretinoin plasma concentrations were measured by a fully validated HPLC method. Special care was taken through the collection and analysis of the samples due to instability of isotretinoin to light and temperature. Pharmacokinetic parameters used to assess bioequivalence were AUC(0-last), AUC(0-infinity) for the extent of absorption and Cmax and Tmax for the rate of absorption. Statistical evaluation of Cmax, AUC(0-last), AUC(0-infinity) was done after semi-logarithmic transformation by 2-way analysis of variance (ANOVA). Tmax values were tested using the distribution-free Hodges-Lehman interval. RESULTS: The parametric 90% confidence intervals for ratio T/R ranged from 95.20-103.20% (point estimate 99.10%) for AUC(0-last), 94.57-102.30% (point estimate 98.36%) for AUC(0-infinity) and 94.81-102.90% (point estimate 98.77%) for Cmax, respectively. Based on the results of Tmax, k(el) and t(1/2), too, there were no statistically significant differences. CONCLUSION: As a result, the 2 isotretinoin preparations in accordance with the European Union bioequivalence requirements, are equivalent with respect to rate and extent of absorption.     

Evaluation of the bioequivalence of two tablet formulations of enalapril/hydrochlorothiazide after single oral administration to healthy volunteers

The pharmacokinetic parameters of two oral formulations of 20/12.5 mg tablets of enalapril/hydrochlorothiazide (CAS 75847-73-3 and CAS 58-93-5, respectively; Penopril as test and another commercially available preparation as reference) were compared in an open-label randomized single oral dose two-period cross-over design to 24 healthy volunteers under fasting conditions. Plasma concentrations of enalaprilat (CAS 76420-72-9), the pharmacologically active metabolite of enalapril, and hydrochlorothiazide were determined by a validated GC/MS and HPLC assay, respectively. Serial blood samples were collected prior to each administration and at 19 timepoints within 36 h after dosing. The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios for enalaprilat were 99.3% to 118.9% (point estimate: 108.7%) for AUC(0-infinity), 97.3% to 116.9% (point estimate: 106.7%) for AUC(0-t), and 92.5% to 113.0% (point estimate: 102.3%) for Cmax, and for hydrochlorothiazide 92.3% to 105.1% (point estimate: 98.5%) for AUC(0-infinity), 92.7% to 105.4% (point estimate: 98.9%) for AUC(0-t), and 97.6% to 115.3% (point estimate: 106.0%) for Cmax, within the acceptance criteria for bioequivalence (80%-125%). Tmax values were analyzed by the nonparametric Wilcoxon test and the difference was not statistically significant. Therefore, it is concluded that the test and reference enalapril/hydrochlorothiazide formulations are bioequivalent for both the extent and the rate of absorption.     

Bioequivalence of two lamivudine tablet formulations

The present study describes the determination of the bioavailability of a new commercial tablet formulation of lamivudine (CAS 134678-17-4) compared with a reference formulation. The comparative bioequivalence of the test and a reference formulation (each 3 x 150 mg) was assessed in 24 healthy volunteers by means of a randomized two-way crossover design. Prior to the study both the test and reference formulations were examined for conformation to chromatographic purity and drug content. Each volunteer received the test (T) and the reference formulation (R) with a one-week drug-free interval between administrations. The plasma concentrations of T were monitored over a period of 12 h after drug administration using a sensitive HPLC method. Pharmacokinetic parameters for T were determined from plasma concentration-time data. Statistical tests were carried out at 90% confidence intervals using a parametric method (three-way ANOVA) for AUC and Cmax, and non-parametric method for Tmax. The present study showed that both formulations were bioequivalent for the geometric mean of AUC(0-12), AUC0-infinity), Cmax, and Tmax at the 90% confidence interval. The bioavailability of the test (%) was 96.7, 93.3, 99.7, 100.3, respectively. The T:R ratio was, in each case, well within the acceptable range of 100 +/- 20%.     

Technological evaluation and equivalence assessment of lorazepam tablets in rabbits

Four different oral lorazepam tablets (Tavor tablets as reference preparation and three generic tablet formulations, A, B and C) were investigated after administration to 12 rabbits to evaluate their bioequivalence. A single 2 mg/kg dose was administered orally as powder and lorazepam plasma concentrations were determined by a validated HPLC method. Maximum plasma concentrations (Cmax), of 207 ng/ml (reference), 198 ng/ml (A), 166 ng/ml (B) and 169 ng/ml (C) were achieved. Lorazepam appeared in the plasma at 0.66 h (Tmax) for all formulations, probably because the disintegration step was bypassed due to the pulverization of the administered doses. Areas under the plasma concentration-time curves (AUC(0-t) and AUC(0-infinity)) were determined. The obtained AUC(0-t) values were 556.57 ng h/ml (reference), 554.70 ng h/ml (A), 493.08 ng h/ml (B), and 487.88 ng h/ml (C). ANOVA results (P > or = 0.05) and 90% confidence intervals for the mean ratio (T/R) of AUC(0-t), AUC(0-infinity), and Cmax were within the EMEA acceptance range. Pharmacokinetic and statistical results of this study show that the four tested drug products (Tavor, A, B, C) are to be considered bioequivalent and interchangeable in medical practice.     

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

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

The effect of acarbose on the pharmacokinetics of rosiglitazone

OBJECTIVES: To investigate whether treatment with acarbose alters the pharmacokinetics (PK) of coadministered rosiglitazone. METHODS: Sixteen healthy volunteers (24-59-years old) received a single 8-mg dose of rosiglitazone on day 1, followed by 7 days of repeat dosing with acarbose [100 mg three times daily (t.i.d.) with meals]. On the last day of acarbose t.i.d. dosing (day 8), a single dose of rosiglitazone was given with the morning dose of acarbose. PK profiles following rosiglitazone dosing on days 1 and 8 were compared, and point estimates (PE) and associated 95% confidence intervals (CI) were calculated. RESULTS: Rosiglitazone absorption [as measured with peak plasma concentration (Cmax) and time to peak concentration (Tmax)] was unaffected by acarbose. The area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was on average 12% lower (95% CI-21%, -2%) during rosiglitazone + acarbose coadministration and was accompanied by an approximate 1-h (23%) reduction in terminal elimination half-life t1/2 (4.9 h versus 3.8 h). This small decrease in AUC(0-infinity) appears to be due to an alteration in systemic clearance of rosiglitazone and not changes in absorption. These observed changes in AUC(0-infinity) and t1/2 are not likely to be clinically relevant. Coadministration of rosiglitazone and acarbose was well tolerated. CONCLUSION: Acarbose administered at therapeutic doses has a small, but clinically insignificant, effect on rosiglitazone pharmacokinetics.     

Evaluation of the bioequivalence and pharmacokinetics of two formulations of rizatriptan after single oral administration in healthy volunteers

The pharmacokinetic parameters of two oral formulations of rizatriptan (CAS 144034-80-0, a capsule preparation as test and rizatriptan tablet as reference), given at a single dose of 10 mg each, were compared in an open-label, randomized, single oral dose, two-period cross-over design in 20 healthy volunteers under fasting conditions. Plasma concentrations of rizatriptan were measured by a validated HPLC assay. The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 91.9% to 101.9% (point estimate: 97.3%) for AUC(0-infinity), 93.0% to 102.2% (point estimate: 96.5%) for AUC(0-t), 90.1% to 100.0% (point estimate: 95.4%) for Cmax, being within the acceptance criteria for bioequivalence (80%-125%). Tmax values were analyzed by the nonparametric Wilcoxon test and the difference was not statistically significant. Therefore, it is concluded that the test and reference rizatriptan formulations are bioequivalent with regard to both the extent and the rate of absorption.     

The bioequivalence study of folifer-Z: a new formulation of sustained-release iron and zinc

The bioequivalence of Folifer-Z tablets, a new sustained-release iron and zinc formulation was evaluated and compared to that of Fefol-Z capsules in 30 healthy male subjects. Each subject received a single oral dose of either product according to a randomized two-way crossover design. A washout period of 1 week was allowed after each treatment. Blood samples were obtained over a 24-h period, and iron and zinc concentrations were measured. The pharmacokinetic parameters of Folifer-Z were Cmax (103 +/- 46.2 micrograms/dl), Tmax (5.93 +/- 2.94 h) and AUC0-24 h (1937 +/- 706 micrograms/dl per h), whereas the corresponding Fefol-Z values were Cmax (109 +/- 41.5 micrograms/dl), Tmax (6.64 +/- 2.54) and AUC0-24 h (1865 +/- 699 micrograms/h per dl). Analysis of variance on log-transformed data for Cmax and AUC0-24 h revealed lack of significant differences among the two formulations. The mean relative bioavailability of AUCtest/AUCreference was 1.07 (90% confidence interval range: 99-115%) and for Cmax test/Cmax reference was 0.96 (90% confidence interval range: 88-105%). Regarding the zinc results, the pharmacokinetic parameters of Folifer-Z values were Cmax (101 +/- 20.7 micrograms/dl), Tmax (4.86 +/- 1.53 h) and AUC0-24 h (1944 +/- 202 micrograms/h per dl), while the corresponding Fefol-Z values were Cmax (102 +/- 20.7), Tmax (4.93 +/- 1.51) and AUC0-24 h (1953 +/- 200). Analysis of variance on log-transformed zinc data for Cmax, Tmax and AUC0-24 h revealed lack of significant difference among the two formulations. The mean relative bioavailability of AUCtest/AUCreference was 0.98 (90% confidence interval range; 95-101%) and for Cmax test/Cmax reference was 0.92 (90% confidence interval range: 89-96%). The results also indicate a possible inhibition of zinc absorption by iron content of both formulations. It is concluded that Folifer-Z product is bioequivalent to Fefol-Z product.