Bioequivalence assessment of two capsule formulations of omeprazole in healthy volunteers

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two omeprazole (CAS 73590-58-6) capsule formulations, Emilok (test) and a commercially available original preparation (reference), under fasting conditions. A 20 mg dose of each formulation was administered to 36 healthy male volunteers with one-week washout period, 17 blood samples were collected over 12 h, plasma omeprazole concentrations were determined by a locally validated high performance liquid chromatography (HPLC) assay, and omeprazole pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD of Cmax, Tmax, AUC(0 --> t), AUC(0 --> infinity), and t1/2 were 0.41 +/- 0.21 and 0.48 +/- 0.27 microg/ml, 1.98 +/- 1.02 and 1.63 +/- 0.78 h, 0.95 +/- 0.78 and 1.00 +/- 0.90 microg x h/ml, 0.99 +/- 0.81 and 1.04 +/- 0.95 microg x h/ml, and 1.30 +/- 0.64 and 1.14 +/- 0.61 h for the test and reference formulations, respectively. The parametric 90% confidence intervals on mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range of 80% to 125% for AUC(0 --> t) and AUC(0 --> infinity) (88.63% to 104.98%, and 91.71% to 106.86%, respectively) but not for Cmax (76.27% to 103.63%). ANOVA revealed significant subject's effect for AUC(0 --> t), AUC(0 --> infinity), Cmax, and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 3.66, 3.92, 1.25, and 1.46, respectively. The results confirm the presence of marked individual variations in the pharmacokinetics of omeprazole and indicate that the two formulations are equivalent in relation to the extent but not the rate of absorption.     

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%.     

Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation

The effect of food on the relative bioavailability of an erythromycin particles-in-tablet formulation was studied in 27 healthy volunteers, using a four-way, crossover study design with the following treatments: one or two erythromycin capsules USP (Eryc, Parke-Davis), or one polymer-coated erythromycin particles-in-tablet (PCE, Abbott) administered fasting or with a high-fat meal. Under fasting conditions the erythromycin particles-in-tablet and erythromycin capsule formulations are bioequivalent based on similar tmax and dose-normalized Cmax and AUC values. The rate and extent of absorption from the particles-in-tablet formulation, however, are dramatically reduced following administration with a meal. Mean Cmax and AUC values decreased by 73% and 72%, respectively, and seven subjects had no detectable erythromycin plasma concentrations for 16 hours following administration of the particles-in-tablet formulation with the high-fat meal. Greater than 40% of the subjects had nonfasting Cmax and AUC values that were less than 10% of those values following administration of the dose fasting. Cmax and AUC values in nonfasting subjects were within 75% to 125% of fasting values in only two and one of 27 subjects, respectively. The erythromycin particles-in-tablet formulation therefore should not be administered with meals.     

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 amoxicillin formulations

A randomized single-dose crossover study was conducted in 24 healthy male volunteers to compare the bioavailability of two amoxicillin (CAS 26787-78-0) formulations, Glomox tablet (test) and a commercially available original preparation, amoxicillin capsule (reference). One thousand milligram of each formulation were administered after an overnight fast with a washout period of three days. Sixteen blood samples were collected over 10 h, amoxicillin concentrations in deproteinized serum were determined by a high performance liquid chromatographic (HPLC) assay, and pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the curve (AUC0-->t and AUC0-->infinity), and elimination half-life (t1/2) were 13.30 +/- 4.52 and 12.99 +/- 3.56 microg/ml, 1.92 +/- 0.76 and 2.02 +/- 0.62 h, 42.50 +/- 13.62 and 42.24 +/- 12.35 microg x h/ml, 46.31 +/- 13.23 and 46.08 +/- 12.14 microg x h/ml, and 1.54 +/- 0.39 and 1.48 +/- 0.48 h for the test and reference formulation, respectively. The parametric 90 % confidence intervals of the mean of the difference (test-reference) between log-transformed values of the two formulations were 92.61% to 109.50%, 92.83% to 109.12%, and 93.11% to 109.41% for AUC0-->t, AUC0-->infinity, and Cmax, respectively. The results indicate that the two formulations can be considered equivalent with regard to the rate and extent of absorption under fasting conditions.     

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.     

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.     

Bioequivalence evaluation of two rosiglitazone tablet formulations

A randomized, two-period, two-sequence, crossover study was conducted on 28 healthy male volunteers to compare the bioavailability of two rosiglita-zone (CAS 122320-73-4) tablet formulations, a test and a commercially available original preparation (reference), under fasting conditions. The two preparations were given in a dose of 8 mg with a 7-day washout period between the two preparations. Eighteen blood samples were collected over 24 h, plasma rosiglitazone concentrations were determined by locally validated high performance liquid chromatography (HPLC) assay, and pharmacokinetic parameters were analyzed by the standard non-compartmental method. The mean+/-SD of AUC0-->t, AUC0-->infinity, Cmax, Tmax, and t1/2 were 4.80+/-1.89 and 4.76 +/-1.94 microg x h/ml, 5.17+/-2.11 and 5.08 +/- 2.27 microg x h/ml, 0.93+/-0.24 and 0.99+/-0.34 microg/ml, 1.0 +/-0.4 and 0.8+/-0.5 h, and 5.0+/-2.0 and 5.0+/-2.0 h for the test and reference formulation, respectively. ANOVA did not show significant formulation, period, or sequence effect for any of the pharmacokinetic parameters. The 90 % confidence intervals of the mean differences between log-transformed values of the two formulations were 93.09 % to 109.73 %, 94.04 % to 111.70 %, and 89.70 % to 103.24 % for AUC0-->t, AUC-->infinity, and Cmax, respectively. It is concluded that the two formulations are equivalent in relation to the rate and extent of absorption.     

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.     

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.     

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.     

Comparative bioavailability of two tablet formulations of fluphenazine dihydrochloride in drug-free psychiatric patients

The comparative bioavailability of a new tablet formulation of fluphenazine dihydrochloride (5 mg) and a reference product (fluphenazine dihydrochloride, Prolixin, 5 mg) was assessed in drug-free psychiatric patients. Twenty-six patients were initially entered in the study, of whom 22 completed the protocol. Each patient received the test (T) and the reference formulation (R) in a balanced two-way crossover design. Plasma concentrations of fluphenazine were monitored over a period of 48 h after drug administration using a sensitive HPLC method. One patient did not show any measurable plasma concentration for one formulation at any sampling time and, therefore, bioavailability was assessed in the remaining 21 patients. All pharmacokinetic parameters showed wide intersubject variation. The maximum plasma concentration (Cmax), time to Cmax, and area under the curve up to the last measurable concentration (AUClast0), infinity (AUCinfinity0), or truncated areas (such as AUC16(0), AUC24(0) were compared by analyses of variance and found not to be significantly different in each case across the formulations. Except for AUC24(0), AUC32(0), and AUC48(0), ANOVA of all other parameters showed a high power (greater than 80%) to detect a 20% difference in the mean value of each bioequivalence parameter between T and R. The two formulations were found to be bioequivalent in that confidence intervals of the mean values of AUCinfinity0, AUClast0, truncated AUCs, or Cmax for T:R ratios were, in each case, well within the acceptable range of 100 +/- 20%.     

Comparative fasting bioavailability and pharmacokinetic properties of 2 formulations of glucosamine hydrochloride in healthy Chinese adult male volunteers

Glucosamine (CAS 66-84-2) hydrochloride is an amino monosaccharide indicated for the treatment of arthrosis, especially osteoarthritis of the knee joint. This study was conducted to assess and compare the pharmacokinetic (PK) properties, bioavailability of a newly developed dispersible tablet formulation (test) of glucosamine hydrochloride with those of an established branded capsule formulation (reference) in healthy Chinese adult male volunteers.This single-dose, randomized, open-label, 2-period crossover study was conducted in 18 healthy Chinese adult male volunteers under fasting condition. Plasma samples were collected at pre-specified times over a 12-h period following administration in each period and analyzed the plasma glucosamine concentrations by Liquid Chromatography coupled with Tandem Mass Spectrometry (LC/MS/MS) method. The mean (SD) PK parameters of Cmax, Tmax, AUC0-12, and AUC0-∞ after administration of the test and reference formulations were, respectively, as follows: Cmax, 907.01 (444.22) vs. 944.40 (429.89) ng/mL, Tmax, 3.03 (0.95) vs. 3.30 (0.99) hours, AUC0-12, 2891.41 (1352.30) vs. 2889.69 (925.48) ng/mL/h, and AUC0-∞, 3029.90 (1321.36) vs. 3091.87 (870.36) ng/mL/h. The mean (SD) t1/2 was 1.10 (0.52) hours for the test formulation and 1.50 (1.17) hours for the reference formulation. On ANOVA, neither period nor sequence effects were observed for any PK properties. The relative bioavailability of the test formulation was 98.3% assessed by AUC0-12. The 90% CIs of glucosamine for the log-transformed ratios of Cmax, AUC0-12, and AUC0-∞ were 78.4-113.9%, 80.8-108.5% and 80.8-105.8%, respectively, meeting the predetermined criteria for bioequivalence of SFDA.     

Formulation dependent pharmacokinetics--does the dosage form matter for nifedipine?

This was an open-label, randomized, 3-way crossover study that compared in 25 healthy male subjects, the pharmacokinetics of a single 60-mg dose of nifedipine GITS tablet versus (1) 20-mg doses of nifedipine prolonged action tablets given q12h for a total of two doses and (2) 2 x 10 mg doses of nifedipine capsules given q8h for a total of three doses. Following capsule administration, there was a rapid rise in plasma concentration of drug achieving a peak concentration of 196(35) ng/mL (mean and coefficient of variation) within 0.7 (105) hours and an AUC(infinity) of 973(39) ng.hr/mL. After nifedipine PA there was also a rapid rise in plasma concentration of drug achieving a Cmax of 85.5 (36) ng/mL with a tmax of 1.7(58) hours and an AUC(infinity) of 879(46) ng.hr/mL. For the nifedipine GITS formulation, there was a lag in the plasma concentration time profile for approximately 2 to 3 hours, then it rose gradually achieving a Cmax of of 686(54) 30.5(63) ng/mL with a tmax of 15.0(50) hours and an AUC(infinity) ng.hr/mL. The AUC(infinity) and Cmax were significantly (P = 0.0001) greater in the capsule and PA formulations than for the GITS; however, the tmax for the GITS formulation was significantly (P = 0.001) longer than for the other formulations.This study suggests marked formulation-dependent pharmacokinetics, which may have important clinical implications.     

Pharmacokinetics and gamma scintigraphy evaluation of two enteric coated formulations of didanosine in healthy volunteers

AIMS: The aims of the study were to evaluate the bioavailability of didanosine from the encapsulated enteric coated beads (1 x 200 mg; enteric beads) and enteric coated mini-tablets (4 x 50 mg; enteric tablet) formulations relative to the chewable/dispersible buffered tablets (2 x 100 mg; buffered tablet), and to study their rate of gastrointestinal transit. METHODS: This was a single-dose, randomized, three-way crossover study in 18 healthy male volunteers. A 200 mg dose of didanosine was given in each period and each formulation contained a gamma radiation-emitting isotope. Pharmacokinetic parameters determined were Cmax, tmax, AUC(0, infinity ) and t1/2. Bioequivalence was assessed using the confidence interval (CI) of 0.80, 1.25 for Cmax and AUC(0, infinity ). Scintigraphic images were recorded and gastrointestinal transit profiles were generated. RESULTS: The point estimate and 90% CI of the ratio of Cmax for the enteric beads and enteric tablet relative to the buffered tablet was 0.71 (0.59, 0.85) and 0.55 (0.46, 0.66), respectively. The tmax was significantly different for the enteric beads (median, 1.33 h) and the enteric tablet (median, 2.83 h) than for the buffered tablet (median, 0.67 h). The AUC(0, infinity ) satisfied the bioequivalence criteria, and the point estimate and 90% CI of the ratio were 1.02 (0.91, 1.15) and 0.92 (0.82, 1.04) for the enteric beads and enteric tablet, respectively. The AUC(0, infinity ) values appeared to be less variable with the enteric beads (% CV = 19%) than with the enteric tablet (% CV = 33%). The t1/2 values were not significantly different between formulations, and the mean values ranged from 1.82 to 1.92 h. Inspection of the individual scintigraphy profiles and concentration-time curves suggested that didanosine was absorbed throughout the small intestine. Gastrointestinal transit parameters were higher for both enteric formulations than for the buffered tablet, indicating slower transit of the enteric formulations. Between the enteric formulations, gastric emptying was slower for the enteric beads than for the enteric tablet; however, plasma didanosine concentrations were observed sooner for the enteric beads, suggesting that the enteric coat for the beads dissolved more rapidly. CONCLUSIONS: The enteric beads and enteric tablet formulations of didanosine were equivalent to the buffered tablet in their extent of absorption. Although the gastric emptying of the enteric tablet was faster, based on the rapid uncoating and the lower variability in AUC, the enteric beads were chosen for further clinical development.     

Bioequivalence of abacavir generic and innovator formulations under fasting and fed conditions

OBJECTIVE: Abacavir sulfate is a synthetic carbocyclic nucleoside analogue indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. The objective of the current study was to determine the bioequivalence between a generic formulation of abacavir and the innovator product. MATERIAL AND METHODS: A total of 80 subjects were randomly assigned to receive a single 300 mg oral dose of abacavir sulfate as the generic (Ranbaxy-Abacavir, Ranbaxy Laboratories Ltd., equivalent to 300 mg of abacavir) and innovator (Ziagen, GlaxoSmithKline) tablet formulations in 2-way crossover studies performed under fasting (n=40) and fed (n=40) conditions. Multiple blood samples were collected over 14 hours and plasma concentrations of abacavir were assayed using an LC/MS/MS method with a limit of quantitation of 25.0 ng/ml. Pharmacokinetic (PK) parameters were calculated using noncompartmental methods. RESULTS: Under fasting conditions, geometric mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), area under the curve extrapolated to infinity (AUC(0-infinity) and maximum plasma concentrations (Cmax) of abacavir for the generic (5565 ng x h/ml, 5668 ng x h/ml and 2526 ng/ml, respectively) and innovator (5675 ng x h/ml, 5770 ng x h/ml and 2528 ng/ml, respectively) products were very similar. Under fed conditions, mean values of AUC(0-t) AUC(0-infinity) and Cmax for the generic (4487 ng x h/ml, 4571 ng x h/ml and 1841 ng/ml, respectively) and innovator (4574 ng x h/ml, 4654 ng x h/ml and 1781 ng/ml, respectively) formulations were also very similar. Ratios of LSM and 90% confidence intervals of PK parameters between the 2 formulations were within 80.0 - 125.0% under fasting and fed conditions, suggesting that the 2 tablet formulations resulted in similar rate and extent of bioavailability. Adverse events for the generic and innovator products were similar in nature and frequency in the fasting and fed studies. CONCLUSIONS Based on the above results, the generic tablet formulation of abacavir developed by Ranbaxy should be equally effective as the innovator product.     

Clarithromycin bioequivalence study of two oral formulations in healthy human volunteers

OBJECTIVE: To assess the bioequivalence of two tablet formulations of clarithromycin (Clamicin 500 mg from Medley Indlistria Farmaceutica, Brazil, as the test formulation, and Biaxin 500 mg from Abbott Industries, USA, as the reference formulation). METHODS: A single 500 mg oral dose of each formulation was administrated in 24 healthy volunteers of both sexes (12 males and 12 females). The study was conducted open, randomized, two-period crossover design with a 7-day interval between doses. The plasma concentrations of clarithromycin were quantified by reversed phase liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM) method. 14-hydroxyclarithromycin concentration was estimated semiquantitatively as equivalent of clarithromycin/ml. The precision of the method was evaluated using calibration curves and plasma quality control samples. The pharmacokinetic parameters calculated for both compounds included: AUC(0 - 48h), AUC(0 - infinity), Cmax, Cmax/AUC(0 - 48h), Tmax, T1/2 and Ke. RESULTS: Standard curves of clarithromycin in plasma were linear in the range of 0.05 microg x ml(-1) to 10 microg x ml(-1) (r > 0.999). The limit of quantification was 5 ng/ml. Within- and between-run plasma quality control CV were 5.8% and 15.7%, respectively. Inaccuracy within- and between-runs were 14% and 17%, respectively. 90% CI for clarithromycin geometric mean AUC(0 - 48h), AUC(0 - infinity) and Cmax ratios (test/reference) were: 8.7% - 103.1%, 89.4% - 103.7% and 85.4% - 99.6%, respectively, and for hydroxyclarithomycin were 80.3% - 108.6%, 80.1% - 110.1% and 85.4% - 112.6%, respectively. CONCLUSION: The method described for the quantification of charithomycin and its main metabolite is accurate and sensitive. Clamicin was considered bio-equivalent to Biaxin based on the rate and extent of absorption. Since these were no significant differences in the bioequivalence determined using the pharmacokinetic parameters of either clarithromycin or 14-hydroxyclarithromycin, we suggest that future bioequivalence trials of this drug may be performed by quantifying clarithromycin only.     

Cyclosporine bioequivalence study: quantification using fluorescence polarization immunoassay (FPIA) and radioimmunoassay (RIA)

OBJECTIVE: The aim of study was to compare the bioavailability of 2 cyclosporine capsule formulations (100 mg; Sigmasporin Microoral from Novaquímica Divis?o Nature's Plus Farmacêutica Ltd., Brazil, as test formulation and Sandimmune Neoral from Novartis Biociências S.A., Brazil, as reference formulation) in 24 healthy male volunteers. METHODS: The study was open, randomized, with a 2-period crossover, a 1-week washout interval between doses. Blood samples were obtained over a 12-hour interval after each oral administration of cyclosporine (2 capsules of 100 mg of each formulation). Cyclosporine blood concentrations were quantified using a fluorescence polarization immunoassay (FPIA) method provided by Abbott Axsym System and Cyclo-Trac SP. Whole-blood radioimmuoassay (RIA) kit was provided by DiaSorin. These assays provided concentration-time curves for cyclosporine in blood concentration from which the following pharmacokinetic parameters were obtained: AUC(last), AUC(inf), Cmax. RESULTS: Geometric mean and 90% confidence intervals (CI) of Microoral/Neoral as percent ratios were 94.5% (90.8-98.4%) for AUC(last), 93.8% (89.7-98.1%) for AUC(inf), and 98.1% (94.5-101.8%) for Cmax when cyclosporine was determined using FPIA and 96.1% (91.9 to 100.6%) for AUC(last), 95.2% (90.2-100.5%) for AUC(inf), and 99.4% (96.4-102.4%) for Cmax using RIA. CONCLUSION: Since the 90% CI for Cmax, AUC(last) and AUC(inf) ratio were within the 80-125% interval proposed by US-FDA, it is concluded that Sigmasporin Microoral 100 mg capsule formulation is bioequivalent to Sandimmune Neoral 100 mg capsule formulation with regard to both rate and the extent of absorption.