生物利用度和生物等效性分析软件简介

考虑生物利用度的影响因素,仿制药物（或制剂）与参比对象采用相同的等效剂量,应能达到生物等效。生物利用度一般用以下几个药代动力学参数衡量：曲线下面积（AUC）,峰浓度（Cmax）,达峰时间（tmax）。本论文以双交叉生物等效性试验为例,介绍自主开发的生物等效性分析软件BA＆BE,该软件使用便捷、界面友好,可用于临床药理和新药研发等相关领域。软件允许用户直接在网格界面进行数据录入,设置变量和参数。系统便可自行对原始数据进行方差分析（ANOVA）、生物利用度和生物等效性的计算并生成报表。该软件将有助于科研人员更迅速、准确地进行数据分析和提交结果。     

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.     

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.     

Nimodipine semi-solid capsules containing solid dispersion for improving dissolution

The aim of this study was to improve the dissolution and, therefore, bioavailability of the poorly water-soluble and highly permeable drug nimodipine (NMD). Present research involved the preparation of a solid dispersion (SD) consisting of NMD, Eudragit-E100 and Plasdone-S630 by hot-melt extrusion (HME). Compared with pure drug and physical mixture, the dissolution of NMD was enhanced dramatically (about 80% within 30min). Adding the nimodipine solid dispersion (NMD-SD) powder to a mixture of Plasdone-S630 and PEG400, and then transferring it to hard HPMC capsules, resulted in nimodipine semi-solid capsules (NMD-SSC). The dissolution from NMD-SSC was increased further (about 95% in 20min). In addition, the relative bioavailability of the NMD-SSC (test) and Nimotop (reference) was determined in beagle dogs after a single dose (120mg NMD) in a randomized crossover, own-control study. The results suggested that there was no significant difference in the areas under the plasma concentration-time curve and the mean peak concentration between NMD-SSC (AUC(0-infinity)=2488+/-433nghmL(-1), Cmax=321+/-78ngml(-1)) and Nimotop (AUC0-infinity=2272+/-398nghmL(-1), Cmax=293+/-73ngmL(-1)) (P>0.05). However, the apparent rate of absorption of NMD from NMD-SSC (tmax=1.3h) was markedly faster than that from Nimotop (tmax=3.1h) (P<0.05), which indicates that as a fast release preparation, NMD-SSC is well absorbed.     

In vitro dissolution and in vivo bioavailability of commercial levothyroxine sodium tablets in the hypothyroid dog model

The objective of this study was to determine whether a correlation exists between the rate of in vitro dissolution and bioavailability of levothyroxine sodium (T4) tablets. Dissolution versus time profiles for Synthroid, the Flint brand of levothyroxine sodium, and two competitors' tablets (brands A and B) were generated using an official dissolution apparatus (USP), and 0.05 M phosphate buffer (pH 7.4) as the medium. These tablets were also utilized in single-dose crossover bioavailability studies in the hypothyroid dog model (n = 6). The average areas under the serum T4 concentration versus time curve from 0 to 8 h (AUC) for Synthroid, brand A, and brand B were 8.22, 6.32, and 8.70 ng-h/mL per dose (micrograms per kg body weight), respectively. Respective peak serum concentrations (Cmax) for each tablet formulation were 1.26, 1.07, and 1.36 ng/mL per dose. The corresponding dissolution rates, expressed as t50%, were 20.5, 3.06, and 14.1 min, respectively. Data analysis indicated no correlation between dissolution kinetic parameters and the bioavailability parameters AUC and Cmax. However, a linear relationship was observed between dissolution kinetics and both the time to reach maximal serum concentration (tmax) and the observed absorption rate constant (ka).     

Inter- and intrasubject variations of ranitidine pharmacokinetics after oral administration to normal male subjects

Inter- and intrasubject variations of ranitidine pharmacokinetics were examined following oral administration of ranitidine tablets (150 mg as base) under controlled conditions at a timed interval of one week (periods I and II) to 12 healthy male subjects. Significant secondary peaks in the plasma concentration-time curves were observed in all subjects in both periods. The first peak occurred at 0.5 to 2.5 h and the second peak at 3 to 6 h after the dosing. There were great variations in the plasma concentration-time profiles among subjects; for example, the area under the plasma concentration-time curve from time 0 to 12 h (AUC0-12) varied from 1905 to 5672 micrograms.h/mL. But bioavailability parameters of period I, such as maximum concentration of the first and second plasma peak (Cmax 1 and Cmax 2, respectively), time to first peak (tmax 1), AUC0-12, and AUC from time zero to infinity (AUC0-infinity), were correlated significantly with those of period II. These results suggest that the intrasubject variation of ranitidine pharmacokinetics is usually small over at least one week under the controlled conditions of this study, in spite of its great intersubject variation.     

Bioequivalence of different prednisolone tablet formulations

The relative bioavailability of different prednisolone (CAS 50-24-8) tablet formulations (Prednisolon Ferring 2, 5, and 20 mg) was investigated in comparison to a reference formulation. The study was performed in a GCP/ICH-conform manner using a randomized cross-over design in 13 healthy volunteers. With respect to the pharmacokinetic parameters Cmax (maximal prednisolone concentration), AUC0-12 h (area under the concentration-time curve until 12 h after drug intake), AUC0-infinity (area under the concentration-time curve until infinity), and t1/2 (elimination half-life time), 10 x 2 mg prednisolone tablets did not show any relevant differences as compared to the reference (1 x 20 mg) meaning that the 90% confidence intervals were within the given 0.80-1.25 limits for the decision of bioequivalence. Although not statistically significant, tmax (time to reach the maximal prednisolone plasma concentration) was 11 min shorter regarding the test preparation as compared to the reference. The pharmacokinetic parameters of 4 x 5 prednisolone tablets were also well in accordance with the reference. The most important parameters Cmax, AUC and t1/2 were within the defined limits for the acceptance of bioequivalence and, in addition, tmax did not show any significant differences. The 20 mg prednisolone tablet formulation showed almost identical parameters of Cmax, AUC, t1/2 und tmax in comparison to the reference substance. Taken together, the results of the bioavailability parameters indicate the bioequivalence of the three prednisolone test preparations as compared to the reference.     

In vitro dissolution and in vivo oral absorption of methylphenidate from a bimodal release formulation in healthy volunteers

PURPOSE: The objective of this study was to evaluate the in vitro dissolution and in vivo absorption of D,L-threo-methylphenidate (MPH) from a novel bimodal release formulation (Ritalin LA capsule) compared with an immediate-release formulation (Ritalin IR tablet) in healthy volunteers. METHODS: The bimodal release formulation contains 50% of the dose in the immediate-release (IR) beads and 50% in polymethacrylate-coated, delayed-release (DR) beads. To better understand the impact of dissolution from the DR beads on oral absorption of MPH, three Ritalin LA formulations with different dissolution profiles for the DR beads (referred to as slow-, medium and fast-release formulations) were prepared, and tested together with the immediate-release formulation in 18 healthy male and female volunteers after a single oral dose under fasted conditions. The rate and extent of oral absorption of MPH were evaluated based on the overall Cmax, tmax and AUC values, as well as the Cmax, tmax and AUC values for each individual peak of the bimodal plasma concentration-time profile. The in vivo absorption-time profile was also examined by deconvolution. RESULTS: All three Ritalin LA formulations demonstrated similar bimodal plasma concentration-time profiles with two peak concentrations observed at approximately 2 and approximately 6 h post dose, mimicking that of Ritalin IR tablets given 4 h apart. Deconvolution results showed that the absorption of MPH was biphasic, with a rapid absorption phase between 0 to approximately 2 h, and a somewhat slower second absorption between approximately 3-6 h, consistent with the in vitro bimodal release characteristics of Ritalin LA formulation. The three Ritalin LA formulations were bioequivalent to one another based on the overall Cmax and AUC values and the corresponding values describing the first and second peaks, although their in vitro dissolution profiles for the DR beads were different. Compared with Ritalin IR, the Ritalin LA formulation demonstrated a similar rate of absorption for the first peak, a lower second Cmax and a higher trough concentration between peaks, as well as similar overall plasma AUC. CONCLUSIONS: Following a single oral drug administration, Ritalin LA demonstrated a two-peak plasma concentration-time profile, similar to that of the IR formulation given 4 h apart, but with less fluctuation in the plasma concentration-time profile. The in vivo biphasic absorption of MPH appeared to be well correlated with the bimodal dissolution characteristics of this new Ritalin LA formulation, and some changes in the dissolution profiles for the DR beads appeared not to affect the overall bioavailability of MPH in humans.     

Comparative bioavailability of silibinin in healthy male volunteers

AIM: To study a comparative bioavailability of Liverman capsule to Legaion capsule and Silymarin tablet (which contain silibinin) in 24 healthy volunteers. VOLUNTEERS AND METHODS: Twenty-four healthy male Korean volunteers received each medicine at the silibinin dose of 120 mg in a 3 x 3 crossover study. There was a 1-week washout period among the doses. Plasma concentrations of silibinin were monitored by a high-performance liquid chromatography for over a period of 12 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the trapezoidal rule extrapolation method. Cmax (maximum plasma drug concentration) and tmax (time to reach a Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf, AUC(0-12h), and Cmax and untransformed tmax. RESULTS: After an oral administration of Liverman capsule, the pharmacokinetic parameters of silibinin, such as AUC(0-12h) (5.59, 4.24 and 13.9 microg/ml x h for Legalon capsule, Silymarin tablet and Liverman capsule, respectively) and AUCinf (6.00, 4.63 and 15.1 microg/ml x h) were significantly greater, Cmax (1.33, 1.13 and 6.04 microg/ml) was significantly higher and tmax (1.83, 2.10 and 0.875 h) was significantly faster than those after Legalon capsule and Silymarin tablet. CONCLUSION: These results indicate that the absorption and the extent of relative oral bioavailability of silibinin after Liverman capsule were significantly faster and greater, respectively, than those after Legalon capsule and Silymarin tablet.     

Bioequivalence study of two perindopril erbumine tablet formulations in healthy volunteers

The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 20 healthy adult male and female subjects under fasting conditions. In this study, one subject withdrew from the study and one reserve subject did not appear at both periods. The pharmacokinetic parameters were assessed based on the concentrations of perindopril (CAS 82834-16-0) and perindoprilat (CAS 95153-31-4) because perindopril has litte pharmacologic activity until hydrolized in the liver into its active metabolite, perindoprilat. The blood samples from 18 subjects were analyzed for plasma concentrations of perindopril and perindoprilat. In each of the two study periods (separated by a washout of three weeks) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 192 h (AUC), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t(1/2)). The geometric mean ratios (90% CI) of the test drug/reference drug for perindopril and perindoprilat were 106.59% (92.97-122.20%) and 100.56% (94.11-107.46%) for AUC,, 106.64% (93.39-121.77%) and 100.88% (95.30-106.80%) for AUCinfo, and 101.23% (87.39-117.27%) and 99.30% (90.42-109.05%) for Cmax, respectively. The 90% confidence intervals calculated for AUCt and Cmax of perindopril and perindoprilat were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two perindopril erbumine tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.     

Clinical pharmacology of dilevalol (III). A pharmacokinetic study of dilevalol in elderly subjects with essential hypertension

Dilevalol (100 mg) was given once daily for 8 days in eight elderly subjects with essential hypertension. Blood samples for plasma dilevalol concentrations were taken during an 8-hour post-drug period following the first and eighth dosages, and the time to maximum concentration (tmax), maximum plasma concentration (Cmax), distribution half-life (t1/2 alpha), elimination half-life (t1/2 beta) and area under the plasma concentration-time curve (AUC) were determined. A wide intra-subject variability was observed in tmax during the repeated administration. A high inter-subject variability was also demonstrated in tmax, Cmax, t1/2 beta and AUC during both observation periods. No significant difference was observed, however, in these pharmacokinetic parameters between the first and eighth dosages. These data indicate that the pharmacokinetic profiles of dilevalol are not altered during 8 days of therapy in elderly subjects with essential hypertension. Since elderly subjects are potentially heterogenous in capacities for handling the drug, the observed variability in pharmacokinetic parameters may reflect the heterogeneity in the sample chosen for examination in the current study.     

Oral bioavailability of griseofulvin from aged griseofulvin:lipid coprecipitates: in vivo studies in rats.

The bioavailabilities of aged coprecipitates of griseofulvin (Gris), dimyristoylphosphatidylcholine (DMPC), or egg phosphatidylcholine (EPC) and cholesterol (CHOL) in rats and correlations with their in vitro dissolution behaviors were determined. In vivo absorption studies of Gris:DMPC (4:1, w/w) or Gris:DMPC:CHOL [4:1(1:0.33 mole ratio)] coprecipitates yielded evidence of a 40% increase in the peak concentration in plasma (Cmax) and a 2.5- to 3-fold decrease in the time to reach Cmax (tmax), compared with those obtained with micronized Gris but a statistically unchanged area under the concentration in plasma--time curve (AUC) when 1-day-aged samples at equivalent doses were used. On the other hand, a 10% decrease in the AUC, a 20% increase in the Cmax, and a three- to fourfold decrease in the tmax were observed for the same formulations aged for 90 days. In comparison, the Cmax produced by the 1-day-aged Gris:EPC:CHOL [4:1(1:0.33 mole ratio)] coprecipitate was the same as that produced by micronized Gris, but the tmax and the AUC were significantly lower; the Cmax produced by the 90-day-aged coprecipitate was 30% higher than that produced by micronized Gris, but the tmax and the AUC remained unchanged. The Gris concentrations after 5 and 30 min (dissolution parameters) and the percent dissolution efficiency also showed excellent correlations with the concentration in plasma after 1 h, the Cmax, and the AUC (in vivo parameters) for all formulations, but the individual in vitro parameters showed poor correlations with the AUC results.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioequivalence study of two fluoxetine capsule formulations in healthy Middle Eastern volunteers

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

Bioequivalence study of tramadol by intramuscular administration in healthy volunteers

Tramadol hydrochloride (CAS 36282-47-0) is a centrally acting analgesic agent binding to mu opiate receptors. The bioavailability of a new tramadol hydrochloride injection (Limadol) was compared with a commercially available reference product by intramuscular administration in twelve healthy Chinese male volunteers by a standard two-way cross-over trial. Each volunteer received a single 100 mg injection of tramadol HCl in each phase. The bioavailability was compared using the area under the plasma concentration-time curve from time 0 to 30 h (AUC0-30), the area under the plasma concentration-time curve from time 0 to infinity (AUC0-infinity), peak plasma concentration (Cmax), and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the Tmax, Cmax, AUC0-30 and AUC0-infinity of the two preparations. It is concluded that test and reference formulations of tramadol hydrochloride are bioequivalent for both the extent and rate of absorption after a single intramuscular injection.     

Comparative bioavailability of two oral sustained-release procainamide products

The bioavailability characteristics of two sustained-release oral procainamide preparations, Procan SR and Pronestyl-SR, were compared in 10 patients with arrhythmias. Each patient was randomly assigned to receive either Procan SR 1 g or Pronestyl-SR 1 g, both administered orally every six hours. The initial drug was continued for 48 hours (eight doses), at which time the second drug, given at the same dosage and dosing interval, was substituted for a 48-hour period. Serum samples for procainamide determination were obtained hourly between 42 and 48 and between 90 and 96 hours after initiation of procainamide therapy. Values for area under the serum concentration-time curve (AUC) during the steady-state dosing interval, maximum serum drug concentration (Cmax), minimum serum drug concentration (Cmin), Cmax:Cmin ratio (representing fluctuations in serum drug concentrations within the dosing interval), and the time to maximum serum drug concentration (tmax) were determined. Mean ( +/- S.D.) tmax values for Procan SR and Pronestyl-SR were 2.2 +/- 0.8 hours and 3.8 +/- 1.1 hours, respectively. Only the differences between tmax values were statistically significant. The study had an 83% chance of detecting a 20% difference in AUC values. The chances of detecting a 20% difference in values for Cmax and Cmin were 62% and 71%, respectively. These two preparations would probably possess similar therapeutic properties when given at the same dosage and dosing schedule; however, studies with larger subject populations are needed to project bioavailability data to the general population.     

The bioequivalence of two nifedipine fluid capsules

Bioequivalence of Two Nifedipine Liquid Capsules Plasma concentration-time profiles of nifedipine were determined in an open, randomised cross-over study on 12 healthy volunteers after application of 10 mg nifedipine as two different soft gelatin capsule preparations. In vitro dissolution tests showed a significant difference between the reference preparation (R) and the generic preparation (P). Maximal nifedipine plasma concentrations (Cmax) measured at tmax (0.6 h, median) for P averaged 87.5 +/- 32.7 micrograms/l, corresponding values for R were 95.4 +/- 41.1 micrograms/l and 0.46 h. Differences in Cmax and tmax values were not statistically significant. Mean areas under the curves AUC(0-10 h) were 128.7 +/- 59.9 micrograms.h/h after p and 123.3 +/- 49.3 micrograms.h/l after R (n.s.). 95% confidence intervals for indices of bioavailability based on AUC and Cmax overlapped, indicating that the two preparations are bioequivalent.     

Effects of H2-receptor antagonists on ethanol metabolism in Japanese volunteers.

The effects of H2-receptor antagonists (cimetidine, ranitidine, and famotidine) on ethanol metabolism were investigated. Neither in aldehyde dehydrogenase (ALDH)-1 deficient subjects nor in those with normal ALDH-1, did the three H2-receptor antagonists and placebo differ in their effects on the pharmacokinetic parameters of ethanol (i.e. peak time (tmax), metabolic rate (k0), peak serum concentration (Cmax), volume of distribution (V) and area under the concentration-time curve (AUC). The AUC of acetaldehyde was slightly but significantly (P less than 0.05) larger only after treatment with cimetidine. Cmax and tmax of acetaldehyde were unchanged.     

Bioequivalence of a generic metformin tablet preparation.

OBJECTIVE: The bioavailability of a generic preparation of metformin (Diabetmin from Hovid Sdn Bhd) was evaluated in comparison with a proprietary product (Glucophage from Lipha Pharma Ltd., UK). PATIENTS AND METHODS: Twenty-four healthy male volunteers participated in the study conducted according to a two-way crossover design. The bioavailability was compared using the parameters total area under the plasma concentration-time curve (AUC0-infinity), peak plasma concentration (Cmax and time to reach peak plasma concentration (Tmax). RESULTS: No statistically significant difference was observed between the values of the two products in all three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic-transformed AUC0-infinity and Cmax values of Diabetmin over those of Glucophage was found to lie between 0.94-1.03 and 0.94-1.06, respectively, being within the acceptable bioequivalence limit of 0.80-1.25. CONCLUSION: These findings indicate that the two preparations are comparable in the extent and rate of absorption. In addition, elimination rate constant (k(e)) and apparent volume of distribution (Vd) were calculated. There was no statistically significant difference between the values of the two preparations in the k(e) and Vd. Moreover, the values are comparable to those reported in the literature.     

Bioequivalence study of two clopidogrel film-coated tablet formulations in healthy volunteers

The present study was performed to compare the bioavailability of two clopidogrel 75 mg film-coated tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 24 healthy adult male and female subjects under fasting condition. The pharmacokinetic parameters were assessed based on the concentrations of clopidogrel (CAS 120202-66-6) parent compound. In each of the two study periods (separated by a washout of one week) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 24 h (AUCt), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax), time needed to achieve the peak plasma concentration (t(max)), and the elimination half life (t1/2). The geometric mean ratios (90% CI) of the test drug/reference drug for clopidogrel parent compound were 95.19% (81.63-110.90%) for AUCt, 95.55% (80.50-113.42%) for AUCinf, and 100.18% (80.87-124.09%) for Cmax. The 90% confidence intervals calculated for AUCt and Cmax of clopidogrel parent compound were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two clopidogrel film-coated tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.     

In vitro and in vivo equivalence of two oral atenolol tablet formulations

A randomised, cross-over, open study of bioequivalence between two different atenolol (CAS 29122-68-7) tablet formulations is presented. An in vitro comparative study between the two formulations was also performed. Both products meet the USP 23 (United States Pharmacopea) specification. The values of similarity factor (f2) and difference factor (f1) obtained ensure sameness or equivalence of the two dissolution curves. Twenty-four healthy volunteers (male/female) participated in the bioequivalence study. Each treatment was given as a single 100-mg tablet following an overnight fast. Atenolol concentrations in plasma were determined up to 30 h after treatment by HPLC. The pharmacokinetic parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity were tested for bioequivalence after logarithmic transformation of data and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following test/reference ratios and their 90% confidence intervals (90% CI): 1.06 (0.99-1.13) for AUC, 1.07 (0.97-1.18) for Cmax, and 0.99 (0.94-1.07) for Cmax/AUC0-infinity. The 90% CI for tmax was 0.91-1.23. All parameters showed bioequivalence between both formulations. A discrete fall in both systolic (SBP) and diastolic (DBP) blood pressure was observed after the drug administration. The fall extent (approximately 11 mmHg in supine position) and the time course of both parameters after the drug administration was similar for both formulations. Minimal values for SBP and DBP were achieved at 6 h after the drug administration for both formulations. Heart rates were also reduced after the administration of both formulations of atenolol in a similar extent (12 b.p.m.) and following a similar time profile (i.e. maximal reductions were observed between 1 and 3 h after the drug administration). It can be concluded that both formulations are equivalent in vitro and in vivo.