Safety, influence on the endometrium, sonographic changes and bleeding profile after 13 cycles with the new drospirenone only pill (DOP) for contraception.

BACKGROUND: The primary objective of the present trial was to assess the endometrial safety of a new oral contraceptive containing 4 mg drospirenone for a total duration of 13 cycles of 28 days each: 24 days of active treatment followed by 4 days placebo treatment per treatment cycle. MATERIALS AND METHODS: This was a single-center, open-label, multiple-dose study on healthy female subjects at risk of pregnancy. Twenty one (= safety population set) pre-menopausal female Caucasian subjects started treatment with the study medication. The mean age was 29.0 years (range 19.0-36.0 years). Four subjects terminated the trial prematurely for the following reasons: on the subject's request (n=2), due to an adverse event (n=1) and due to loss of contact (n=1). Seventeen subjects completed the planned duration of 13 cycles of open treatment with the test product (each cycle of 28 days). RESULTS: At visit 1 (pre-treatment), the biopsy result in the safety population set was proliferative in 14 cases and secretory in seven cases. At visit 7, four cases showed an inadequate result (insufficient tissue for diagnosis), 12 as proliferative and three as secretory. The number of biopsies with proliferative and secretory results reduced under treatment (safety population). The pre-post treatment changes in the endometrial biopsy results in the treatment completers set (n=17) showed almost no differences. At visit 1 (pre-treatment), the biopsy result was proliferative in 12 cases and secretory in five cases. At visit 7 (after 13 cycles of 28 days), four cases showed an inadequate result (insufficient tissue for diagnosis), 11 as proliferative, and two as secretory. The mean endometrial thickness in the safety population was reduced from 8.3 mm at visit 1 to 6.0 mm at visit 7. When comparing the endometrial thickness in the 21 subjects (safety population), the endometrial thickness showed a pre-post difference of 2.1 mm, whereas the endometrial thickness in the 17 study completers showed a pre-post difference of 2.5 mm (8.2 mm at visit 1-5.6 mm at visit 7). CONCLUSIONS: Drospirenone 4 mg film-coated tablet in a dosage regime of 24/4 days is, regarding endometrial histology, a safe drug. Trial registration: EudraCT Register number: 2013-002300-13.

Pharmacodynamic equivalence study of two preparations of eye drops containing dorzolamide and timolol in healthy volunteers.

OBJECTIVE: The aim of the present study was to assess the pharmacodynamic equivalence (lowering of intraocular pressure) of two preparations of eye drops containing 20 mg dorzolamide (CAS 120279-96-1) and 5 mg timolol (CAS 26839-75-8). METHOD: The study was conducted as a monocentric, observer-blinded, randomized, single-dose, two-period crossover study in 38 healthy volunteers. Each volunteer received on day 1 in each period in a random way a single dose of 1 drop of the test or the reference formulation in the conjunctival sac of the right eye separated by a wash-out period of 7 days. Measurement of intraocular pressure (IOP) of the right eye (by a blinded observer) was performed on day 1 of each study period pre-dose and 2 h post dosing by means of Goldmann applanation tonometry. In order to investigate the pharmacodynamic equivalence of both products, the two-sided 95% confidence interval was calculated for the difference of the primary target parameter (absolute decrease in IOP 2 h post dose), by means of a parametric (ANOVA) statistical method. RESULTS: The results of the statistical evaluation of the primary target parameter "absolute decrease in IOP 2 h post dose" demonstrated a decrease in the IOP of 4.72 mmHg for the eye treated with the test formulation (dorzolamide 20 mg/ml + timolol 5 mg/ml eye drops) and 4.61 mmHg for the treated with the reference formulation. The mean difference was 0.11 mmHg. The 95% confidence interval was between -0.33 and 0.55 mmHg and thus entirely within the pre-defined equivalence range (+/- 1.5 mmHg). The results of the statistical evaluation of the secondary target parameter relative (as % of baseline) decrease in IOP 2 h post dose demonstrated essentially similar effectiveness in lowering the IOP by 27.63% (test formulation) and 27.12% (reference formulation), respectively. Both drug products were well tolerated. CONCLUSION: Both formulations showed comparable results obtained at a time probably equal to the maximum effect concerning the primary target parameter lowering of IOP 2 h post dose. The safety profile of both preparations showed no difference.

Switching epoetin alfa and epoetin zeta in patients with renal anemia on dialysis: Posthoc analysis.

INTRODUCTION: epoetin zeta is a recently introduced recombinant erythropoietin, designed to be biologically similar to epoetin alfa. This posthoc analysis evaluated the impact of switching patients with chronic kidney disease (CKD) on hemodialysis from epoetin alfa to epoetin zeta, or vice versa, on hemoglobin concentration, epoetin dose, and patient safety. METHODS: data were analyzed from three published trials: two 24-week randomized, double-blind (maintenance and induction) studies and a 56-week, open-label, follow-on study involving adult patients with CKD stage 5, maintained on hemodialysis, and receiving epoetin alfa or epoetin zeta. Patients had either completed and switched treatments within the maintenance study, or had completed the induction or maintenance study on epoetin alfa and then switched to, and completed at least 12 weeks of follow-up treatment on, epoetin zeta. Mean hemoglobin levels and epoetin dose were evaluated pre- (0-4 weeks before) and post- (8-12 weeks after) switch, and were considered equivalent for the two treatments if the upper and lower limits of the 95% confidence intervals (CIs) for the intraindividual differences in mean values fell within accepted limits. RESULTS: overall, 481 patients were included in the analysis. Mean hemoglobin concentration was maintained at target levels (10.5-12.5 g/dL) throughout the drug switch. The mean differences in hemoglobin concentration and associated 95% CIs following the switch remained within prespecified equivalence limits (± 1.0 g/dL). The 95% CIs of the mean difference in weekly epoetin dose postswitch also remained within prespecified equivalence margins (± 45 IU/kg; upper limit 17.83 IU/kg, lower limit -10.91 IU/kg). Both treatments were similarly well tolerated. CONCLUSION: our data suggest that epoetin alfa and epoetin zeta therapy can be interchanged without any clinically significant alteration in efficacy, safety, or epoetin dose, in patients with CKD on dialysis receiving stable epoetin maintenance therapy.

Therapeutic equivalence of epoetin zeta and alfa, administered subcutaneously, for maintenance treatment of renal anemia.

INTRODUCTION: The primary objective of the trial was to prove the therapeutic equivalence of epoetin zeta to epoetin alfa when administered subcutaneously for maintaining target hemoglobin (Hb) in patients with renal anemia on chronic hemodialysis. Additional information was provided on the safety and tolerability of epoetin zeta with particular focus on the formation of anti-erythropoietin antibodies. METHODS: A total of 462 patients were randomized to either epoetin zeta or alfa for 28 weeks after an open period of dose adjustment of 12-16 weeks with only epoetin zeta. The aim of treatment was to maintain Hb between 10.0-12.0 g/dL with constant epoetin dosage. Primary endpoints were the mean Hb level and the mean weekly epoetin dosage during the last 4 weeks of treatment. Safety endpoints were the occurrence of anti-erythropoietin antibodies, incidence of Hb levels above 13 g/dL, ratings of tolerability, and adverse events (AEs). RESULTS: The mean Hb level (+/-SD) during the last 4 weeks of treatment was 10.94+/-0.84 g/dL (epoetin zeta) and 11.02+/-0.94 g/dL (epoetin alfa). The 95% confidence interval (CI) (''C0.28 g/dL to 0.12 g/dL) was entirely within the predefined equivalence range (+/-0.5 g/dL). The mean weekly epoetin dosage per body weight over the last 4 weeks of treatment was 97.0+/-94.3 IU/kg/week (epoetin zeta) and 86.0+/-78.0 IU/kg/week (epoetin alfa). The 95% CI (''C8.06 IU/kg/week to 29.96 IU/kg/week) was also within the predefined equivalence range of +/-45 IU/kg/week. The most common AEs were infections and infestations (15.1% of patients on epoetin zeta and 14.8% of patients on epoetin alfa). None of the patients developed anti-erythropoietin antibodies. CONCLUSIONS: Epoetin zeta, administered subcutaneously, is equivalent to epoetin alfa in respect of its clinical efficacy. The safety profile of both products is similar: no unexpected AEs were observed, no patients developed anti-erythropoietin antibodies, and both epoetin preparations were well tolerated.

Therapeutic effects of epoetin zeta in the treatment of chemotherapy-induced anaemia.

OBJECTIVE: To perform an open, non-controlled, multiple-dose, international, multicentre, phase III study to evaluate epoetin zeta, a biosimilar epoetin referenced to epoetin alfa, for the treatment of chemotherapy-induced anaemia in patients with cancer. METHODS: Safety, tolerability and efficacy of subcutaneously administered epoetin zeta were assessed in 216 patients with solid tumours or non-myeloid haematological malignancies receiving chemotherapy and at risk of transfusion. RESULTS: A significant (p < 0.0001) increase in mean haemoglobin (Hb) level (1.8 g/dL) was observed between baseline and week 12 (intent-to-treat population); 176/216 (81.5%) patients achieved a response (increase in Hb > or = 1 g/dL or reticulocyte count > or = 40,000 cells/microL) by week 8. Over the treatment period, 231 treatment-emergent adverse events were experienced by 91 patients; 9/216 (4.2%) experienced a clinically significant thrombotic event within the first 12 weeks of epoetin zeta treatment, significantly lower than the assumed 18% baseline incidence (p < 0.0001) based on historical data from epoetin trials. No transfusion was necessary for 175/216 patients (81.0%) and quality of life improved over the study. No patients developed anti-erythropoietin antibodies. Sponsor trial no: CT-830-05-0009. CONCLUSION: This study demonstrates that subcutaneously administered epoetin zeta is well-tolerated and has efficacy in the treatment of anaemia in patients with cancer receiving chemotherapy and at risk of transfusion.

Influence of acarbose on blood glucose and breath hydrogen after carbohydrate load with sucrose or starch.

A monocentric, open, randomised, single-dose, six-period crossover trial was carried out in healthy volunteers under fasting conditions to establish the most appropriate study design for a pivotal bioequivalence trial with acarbose (CAS 56180-94-0) regarding a) dosage of the drug, b) type of carbohydrate load, c) type of primary endpoint, and d) sample size. 50 g sucrose or 50 g starch were used as carbohydrate load. Acarbose was administered in doses of 50 and 200 mg. Blood glucose and breath hydrogen were evaluated as endpoints. Both acarbose doses reduced the effect of carbohydrate load. Blood glucose: no statistically significant difference could be noted between the overall effect of 50 mg and that of 200 mg acarbose irrespective of the type of carbohydrate load. Breath hydrogen: an influence could be shown only for sucrose as carbohydrate load. Practically no effect was observed with starch. The overall increase of effect is by more than 200% with sucrose when the dose of acarbose increases from 50 to 200 mg. This difference between the effects of both doses of acarbose on breath hydrogen is statistically significant. For a pivotal trial, sucrose is the most appropriate type of carbohydrate load, baseline adjusted area under the breath hydrogen response is the most appropriate primary endpoint, and a dose of 100 mg acarbose is the most appropriate dosage. A total number of 100 subjects will be needed for proving pharmacodynamic equivalence between two acarbose products in a pivotal trial.

Bioequivalence study of two different clopidogrel bisulfate film-coated tablets.

OBJECTIVE: The aim of the present study was to evaluate the bioequivalence of two oral clopidogrel (CAS 113665-84-2) formulations. METHOD: The study was conducted as a monocentric, open, randomized, single-dose, two-period crossover trial in 48 healthy volunteers with a duration of hospitalization of approximately 24 h after dosing on day 1 and with a real wash-out period of 7 days. Blood samples were collected for 24 h post dosing in each period. The plasma was separated and the concentrations of clopidogrel were determined by a LC-MS/MS method. AUC(0-tlast), Cmax, tmax, AUC(0-inf), MRT and t1/2 were calculated for both formulations. RESULTS: The arithmetic means of AUC(0-tlast) and Cmax were 3,656.01 pg x h/ml and 1970.22 pg/ml for the test formulation and 3771.51 pg x h/ml and 1756.52 pg/ml, respectively, for the reference formulation. The mean tmax was 1.16 h for the test and 1.13 h for the reference formulation. The point estimators of the ratios of the test and reference formulations for AUC(0-tlast) and Cmax were 1.042 and 1.115, respectively. Furthermore, the 90% confidence intervals calculated by means of ANOVA-log for the first primary endpoint of the trial, the intra-individual ratio (T/R) of AUC(0-tlast) of clopidogrel was between 0.932 and 1.165. The 90% confidence interval calculated by means of ANOVA-log for Cmax of clopidogrel was between 0.973 and 1.277. The 90% confidence intervals for both parameters were within the predefined acceptance ranges (0.80-1.25 for AUC(0-tlast) and 0.75-1.33 for Cmax). The intraindividual coefficients of variation determined by means of ANOVA-log were 33.51% for AUC(0-tlast) and 41.29% for Cmax. CONCLUSION: While both products were bioequivalent in terms of the rate and extent of absorption, the present study also confirmed a high variability for clopidogrel suggesting high volunteer numbers in bioequivalence trials.

The use of truncated area under the curves in the bioequivalence evaluation of long half-life drugs. Studies with donepezil and memantine.

The bioequivalence of long terminal half-life drugs, donepezil (CAS 120014-06-4) 10 mg and memantine (CAS 19982-08-2) 10 mg, was evaluated by comparing the results obtained for the total areas under the concentration time curves (AUC(0-inf)) with those for partial AUCs: AUC(0-216h), AUC(0-72h) and AUC(0-48h). Pharmacokinetic endpoints were determined by standard formulas from the concentration-time courses of the parent compounds donepezil and memantine. The results of the bioequivalence assessment based on the 90% confidence intervals calculated by means of ANOVA for logarithmically transformed values (ANOVA log) led to exactly the same decision irrespective of the type of AUC used. The 90% confidence intervals for all types of AUCs were practically identical within each product. These results prove that truncated AUCs, e.g. AUC(0-72h) or even AUC(0-48h), can be adequately used in assessing the relative bioavailability of long terminal half-life drugs. The findings suggest that even for drugs with half-lives between 24 and 60 h and thus shorter than those of donepezil and memantine an AUC truncated to 48 h post dose can be successfully used for the assessment of bioequivalence as this sample collection time ensures a proper comparison of the absorption process as recommended in the CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence.

Comparison of the therapeutic effects of epoetin zeta to epoetin alfa in the maintenance phase of renal anaemia treatment.

OBJECTIVE: To evaluate the therapeutic efficacy and safety of epoetin zeta, compared with epoetin alfa, in maintaining target haemoglobin (Hb) concentrations in patients with anaemia and chronic kidney disease (CKD) maintained on haemodialysis. METHODS: Patients received epoetin zeta or epoetin alfa intravenously, 1-3 times/week for 12 weeks, then the alternative treatment for 12 weeks, in this double-blind, crossover, phase III trial. Eligible patients were 18-75 years old with CKD stage 5 maintained on haemodialysis. Patients had received epoetin for > or = 3 months upon study entry and had achieved a target Hb level of 10.5-12.5 g/dL with a stable epoetin dose. MAIN OUTCOME MEASURES: Primary efficacy endpoints were intra-individual differences (test-reference) in mean Hb levels and mean weekly dose/kg of body weight. Safety endpoints included occurrence of neutralizing anti-erythro poietin antibodies, tolerability, and adverse events (AEs). RESULTS: In total, 313 patients were randomized to receive epoetin zeta (n = 155) or epoetin alfa (n = 158); 146 and 145 patients (respectively) switched treatment after 12 weeks. Mean (range) Hb levels were 11.35 (8.96-14.22) g/dL and 11.54 (8.74-13.84) g/dL for patients receiving epoetin zeta and epoetin alfa, respectively (95% confidence interval [CI] [test-reference]: 0.09-0.28 g/dL, within the predefined equivalence range of +/-0.6 g/dL). Mean (range) weekly doses were 92.68 (12.74-398.41) IU/kg/wk and 92.58 (10.53-393.07) IU/kg/wk for patients receiving epoetin zeta and epoetin alfa, respectively (95% CI [test-reference]: -4.67 and 4.29 IU/kg/wk, within the equivalence range of +/-45.00 IU/kg/wk). Patients underwent minor nominal dose adjustments during treatment crossover. AE profile was similar for both products; the most commonly reported AEs were infections and infestations (in 26.5% of patients receiving epoetin zeta and 23.6% receiving epoetin alfa). No patients developed neutralizing anti-erythropoietin antibodies. CONCLUSIONS: Epoetin zeta is therapeutically equivalent to epoetin alfa in the maintenance of target Hb levels in patients with renal anaemia. No unexpected AEs were seen.

Comparison of the therapeutic effects of epoetin zeta and epoetin alpha in the correction of renal anaemia.

OBJECTIVE: To assess the therapeutic equivalence of epoetin zeta and epoetin alpha for correction of haemoglobin (Hb) concentration in patients with anaemia and chronic kidney disease (CKD) stage 5 maintained on haemodialysis. STUDY DESIGN: In total, 609 patients with CKD and anaemia (Hb < 9 g/dL) were randomly assigned to receive either epoetin zeta or epoetin alpha intravenously, one to three times per week for 24 weeks. Dosing was titrated individually to achieve a stable, target Hb concentration of 11-12 g/dL. Primary endpoints were the mean weekly dose of epoetin per kilogram of body weight and mean Hb concentration during the last 4 weeks of treatment. Safety endpoints were the occurrence of anti-erythropoietin antibodies, ratings of tolerability and adverse events (AEs). RESULTS: Mean (+/- standard deviation [SD]) Hb concentration over the last 4 weeks of treatment was 11.61 +/- 1.27 g/dL for patients receiving epoetin zeta, compared with 11.63 +/- 1.37 g/dL for patients receiving epoetin alpha (95% confidence interval [CI]: -0.25 to 0.20 g/dL). Mean (+/- SD) epoetin zeta weekly dose over the last 4 weeks of treatment was 182.20 +/- 118.11 IU/kg/wk, compared with 166.14 +/- 109.85 IU/kg/wk for epoetin alpha (95% CI: -3.21 to 35.34 IU/kg/wk). The most commonly reported AEs (> 5% of patients) were infections and infestations (12.5% and 12.8% of patients treated with epoetin zeta and epoetin alpha, respectively) and vascular disorders (8.5% and 8.9%, respectively). No patients developed neutralizing anti-erythropoietin antibodies. CONCLUSIONS: Epoetin zeta, administered intravenously, is therapeutically equivalent to epoetin alpha in the correction of low Hb concentration in patients with CKD undergoing haemodialysis. No unexpected AEs were seen and both epoetin zeta and epoetin alpha were well tolerated.

Long-term safety and tolerability of epoetin zeta, administered intravenously, for maintenance treatment of renal anemia.

INTRODUCTION: The aim of this trial was to gather data on the long-term safety of a new erythropoietin preparation (epoetin zeta), focusing on the formation of anti-erythropoietin antibodies, when administered intravenously for maintenance of target hemoglobin concentration in anemic patients with end-stage renal failure receiving chronic hemodialysis. In addition, we aimed to provide information on the efficacy of epoetin zeta under open, noncontrolled conditions. METHODS: Patients received epoetin zeta intravenously, 1-3 times/week for 56 weeks (overall patient group, n=745) or 108 weeks (Bulgarian subgroup, n=164). The aim of treatment was to maintain hemoglobin values between 10.5 and 12.5 g/dL with constant epoetin dosage. Primary (safety) endpoints were the occurrence of anti-erythropoietin antibodies and the evaluation of adverse events (AEs). Secondary (efficacy) endpoints included the mean weekly dose of epoetin per kg of body weight and mean hemoglobin concentrations. RESULTS: No patients developed neutralizing anti-erythropoietin antibodies. The most commonly reported AEs were infections and infestations (34.1%); followed by injury, poisoning, and procedural complications (25.8%); and gastrointestinal disorders (21.9%); 37.3% of patients reported serious AEs. The hemoglobin values remained stable, with mean values after 56 weeks of 11.3-11.6 g/dL for the overall group and 11.1-11.6 g/dL for the Bulgarian subgroup. The dosage of epoetin zeta was stable throughout the course of the trial. No cases of lack of (or loss of ) efficacy were observed in the course of the trial. CONCLUSIONS: The evaluation of the primary endpoints provided data supporting the intravenous administration of epoetin zeta in patients with chronic renal failure. Neutralizing antibodies against erythropoietin were not detected, and there were no reports of patients with increasing erythropoietin resistance. Our results suggest that intravenous administration of epoetin zeta is effective regarding its ability to maintain stabilized hemoglobin levels within the target range of 10.5-12.5 g/dL.

Evaluation of the pharmacokinetics of two recombinant human erythropoietin preparations: epoetin zeta and epoetin alfa. 1st Communication: A monocentric, open, randomized, single dose, two-period crossover trial in healthy volunteers.

The pharmacokinetic properties of a new recombinant erythropoietin preparation (epoetin zeta, CAS 604802-70-2) compared to a reference product (epoetin alfa, CAS 113427-24-0) were analyzed after a single intravenous bolus injection of 10,000 IU in a two-period crossover design in 24 healthy volunteers. Peripheral venous blood samples were obtained pre-dose, and 0:05, 0:20, 0:40, 1:00, 1:20, 1:40, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00, 36:00, 48:00, and 72:00 hours post dosing. Samples of 24 volunteers were analyzed by means of a specific immunoassay (ELISA). Three volunteers were excluded from statistical analysis due to a paravasal injection in one of both study periods with resulting low plasma levels of epoetin. Comparison of both preparations showed nearly identical pharmacokinetic properties after intravenous administration. The usual bioequivalence limits were fulfilled for all relevant pharmacokinetic parameters.

Evaluation of the pharmacokinetics of two recombinant human erythropoietin preparations: epoetin zeta and epoetin alfa. 2nd Communication: A monocentric, double-blind, randomized, single dose, three-period crossover trial in healthy volunteers.

The subcutaneous bioavailability of a new recombinant erythropoietin preparation (epoetin zeta, CAS 604802-70-2) and the pharmacokinetic properties of this drug compared to a reference product (epoetin alfa, CAS 113427-24-0) were analyzed after a single intravenous bolus injection or subcutaneous injection of 10,000 IU in a three-period crossover design in 48 healthy volunteers. Peripheral venous blood samples were obtained pre-dose, and 0:05, 0:20, 0:40, 1:00, 1:20, 1:40, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00, 36:00, 48:00, and 72:00 h post dosing. Samples from 48 volunteers were analyzed by means of a specific immunoassay (ELISA). The systemic bioavailability of epoetin zeta after subcutaneous administration is approximately 24%. Comparison of both preparations showed nearly identical pharmacokinetic properties after subcutaneous administration. The usual bioequivalence limits were fulfilled for all relevant pharmacokinetic parameters.

Enhanced plasma concentration by selective deuteration of rofecoxib in rats.

The plasma concentrations of BDD-11602 (4-[4- (methanesulfonyl)phenyl]-3-(pentadeuterophenyl)-5H-furan-2-one), a rofecoxib derivative in which the positions 2',3;4',5' and 6' of the phenyl ring were deuterated, and rofecoxib (4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one, CAS 162011-90-7) were compared in order to explore the effects of selective deuteration on the systemic availability. The COX-2 selectivity in vitro was also compared. Following oral gavage administration of 0.1, 1 or 10 mg/kg BDD-11602 to Sprague Dawley rats, AUCo-t, (area under the curve) and Cmax (maximum concentration) values were statistically significant higher than those of rofecoxib at the same doses. The overall increase in AUC0-t and Cmax for BDD-11602 over rofecoxib was 1.53-fold and 1.60-fold, respectively. BDD-11602 and rofecoxib inhibited COX-2-derived PGE(2) synthesis with IC50 values of 173 nmol/l and 169 nmol/l, respectively. IC50 values for inhibition of human platelet COX-1 were estimated to be above 1 micromol/l for both compounds. The substitution of hydrogen by deuterium on the positions 2: 3',4',5' and 6' in BDD-11602 leads to superior oral availability compared to the non-deuterated compound, whereas the COX-2 selectivity is not affected.

Bioequivalence study of levothyroxine tablets compared to reference tablets and an oral solution.

The study was designed to evaluate the bioequivalence of three levothyroxine sodium (CAS 51-48-9) formulations, i.e. a test and a reference tablet and an oral solution. A bioequivalence study was carried out in 25 healthy volunteers, who were administered a single dose of 600 microg levothyroxine in the form of the test formulation (levothyroxine sodium tablets 200 microg; Eferox), the originator product, and an oral solution. The trial was performed in one study center according to an open, randomized, three-way cross-over design with wash-out periods of 35 days between administration. Blood samples were taken up to 48 h post dose, the plasma was separated and the concentrations of levothyroxine and triiodothyronine were determined by radioimmunoassay with I125 labeling method. The levothyroxine mean Cmax were 112.0+/-17.3 ng/ml, 113.4+/-18.5 ng/ ml and 111.3+/-15.1 ng/ml, while the mean AUC0-24 were 2263.7+/-332.8 ng x h/ ml, 2307.3+/-351.3 ng x h/ml and 2286.1+/-331.0 ng x h/ml for the test and reference tablets as well as for the oral solution, respectively. No significant differences were found of principal pharmacokinetic parameters between the studied formulations. The 90%-confidence interval for the primary target parameters, intra-individual ratios of AUC0-24 and Cmax of levothyroxine were within the acceptance ranges for bioequivalence trials, i.e. AUC0-24 0.954-1.016 and 0.966-1.011 as well as Cmax 0.948-1.027 and 0.968-1.032 for test tablets versus reference tablets and the oral solution, respectively. Similar results were observed for triiodothyronine. In the light of the present study it can be concluded that the levothyroxine test tablet is bioequivalent to the reference formulation in respect of extent and rate of absorption. The results of the present trial confirm the findings of a previous study, performed under steady-state conditions with Eferox tablets 100 microg in patients without thyroid function.

Assessment of the bioequivalence of different formulations containing azithromycin (tablets and suspension).

Azithromycin (CAS 11772-70-0) is an orally administered macrolide antimicrobial drug, structurally related to erythromycin, with a similar spectrum of antimicrobial activity. The aim of the present studies, performed in two different groups of volunteers, was to compare the bioavailability of azithromycin (Azro) 500 mg tablets (study 1) and azithromycin (Azro) 200 mg/5 mL suspensions (study 2) with originator products. Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in 24 healthy volunteers with a wash-out period from 14 to 21 days. Blood samples were taken up to 96 h post dosing, and concentrations of azithromycin were determined by HPLC method. In the first study, the 90% confidence interval for intra-individual ratios (test vs. reference) of AUC0-t and Cmax of azithromycin were between 0.82 and 1.04 for AUC0-t and 0.81 and 1.11 for Cmax, and thus within the acceptance ranges for bioequivalence trials. The 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of azithromycin administered as suspension were between 0.89 and 1.22 and 0.91 and 1.23, respectively. These values were also within the acceptance range. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences for azithromycin were between -0.49 - 0.50 in the first and between -0.50 - 0.25 in the second study, respectively. In the light of the results of the studies reported here it can be concluded that azithromycin test formulations, i.e. tablet and suspension are bioequivalent to the respective reference formulations.

Bioequivalence study of atorvastatin tablets.

The study was designed to evaluate the relative bioavailability of two formulations of atorvastatin (CAS 134523-03-8). A bioequivalence study was carried out in 24 healthy male volunteers who received four 10 mg tablets of the test formulation (Kolestor) and the same dose of the originator product. The trial was performed according to an open, crossover design with a wash-out period of 7 days in one study center. Blood samples were taken up to 48 h post dose, the plasma was separated and the concentrations of atorvastatin were determined by HPLC-MS-MS method. The mean Cmax were 16.37 ng/mL and 17.05 ng/mL, while the mean AUC0-t were 103.61 ng x h/mL and 102.55 ng x h/mL for the test and reference formulations, respectively. The mean AUC0-inf were 118.10 ng x h/mL and 117.13 ng x h/mL for the test and reference formulations, respectively. The median tmax was 0.67 h for both the test tablet and the reference product. The mean t(1/2 el) was 11.85 h for the test formulation and 13.28 h for the reference formulation. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence intervals for the primary target parameters, intra-individual ratios of AUC0-t and Cmax of atorvastatin, were between 0.85 and 1.05 (AUC0-t) and between 0.84 and 1.23 (Cmax), respectively, and thus within the acceptance ranges. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences was between -0.17 and 0.17 h. In the light of the present study it can be concluded that the two evaluated atorvastatin formulations, i.e. test formulation of atorvastatin and reference preparation are bioequivalent in terms of the rate and extent of absorption.

Studies on the bioequivalence of second generation cephalosporins: cefaclor capsules and suspension.

The aim of the present studies, performed in two different groups of volunteers, was to prove the bioequivalence of 500 mg cefaclor (CAS 70356-03-5) test and reference capsules (Losefar 500 mg Capsules as test and an originator product as reference; study 1) and cefaclor 250 mg/5 mL test and reference suspensions (Losefar 250 mg/5 mL Granules oral suspension as test and an originator product as reference; study 2). Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 8 h post dosing, and concentrations of cefaclor were determined by HPLC method. In the first study, the 90% confidence intervals for intra-individual ratios of AUC0-t and Cmax of cefaclor were 0.99-1.08 for AUC0-t and 0.82-1.06 for Cmax, and thus within the acceptance ranges for bioequivalence trials. The 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of cefaclor administered as suspensions were 1.10-1.19 and 1.02-1.21, respectively. These values were also within the acceptance range. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences for cefaclor were between -0.13 - 0.13 in the first and between 0.00 - 0.13 in the second study, respectively. In the light of the results of the studies reported here it can be concluded that cefaclor test formulations, i.e. capsules and suspension are bioequivalent to the respective reference formulations.

Studies on the bioequivalence of different strengths of tablets containing clarithromycin.

The aim of the present studies, performed in two different groups of volunteers, was to compare the bioavailability of clarithromycin (CAS 81103-11-9) tablets (Klaromin, test tablets) containing 250 mg (study 1) or 500 mg (study 2) of the drug with reference tablets of the same strength. Each study was conducted according to an open, randomized, single-dose, two-period crossover design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 24 h in both studies, and concentrations of clarithromycin and its principal active 14-hydroxy metabolite were determined by HPLC method. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of clarithromycin were between 0.93 and 1.05 (AUC0-t) as well as between 0.90 and 1.18 (Cmax). In the second study, i.e. after administration of clarithromycin 500 mg tablets, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of clarithromycin were between 0.90 and 1.08 (AUC0-t) as well as between 0.85 and 1.22 (Cmax). All these values were within the acceptance ranges for bioequivalence studies. In both studies, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of 14-hydroxy-clarithromycin were also within the acceptance ranges, although the confidence intervals for these parameters were not planned to be compared with the acceptance ranges. In the light of the results of the studies reported here it can be concluded that the clarithromycin 250 mg and 500 mg test tablets are bioequivalent to the respective reference formulations.

Clarithromycin suspension: bioequivalence studies on two different strengths.

Two studies were performed in different groups of volunteers, with the aim to prove the bioequivalence of test (Klaromin) and reference clarithromycin (CAS 81103-11-9) suspensions containing in 5 mL either 125 mg (study 1) or 250 mg (study 2) of the drug, administered as an oral dose of 10 mL. Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 24 h in both studies, and concentrations of clarithromycin and its principal active 14-hydroxy metabolite were determined by HPLC. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of clarithromycin were between 0.84 and 1.03 (AUC0-t) and between 0.89 and 1.03 (Cmax). In the second study, i.e. after administration of clarithromycin suspension 250mg/5mL, the 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of clarithromycin were between 1.01 and 1.17 (AUC0-inf) and between 1.01 and 1.16 (Cmax). All these values were within the acceptance ranges for bioequivalence studies. In both studies, the 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of 14-hydroxy-clarithromycin were also within the acceptance ranges. In the light of the results of the studies reported here it can be concluded that the clarithromycin test formulations are bioequivalent to the respective reference formulations, i.e. suspensions containing 125 mg/5 mL and 250 mg/5 mL of the drug.