Rita Neves

Results of a single-center, single-dose, randomized-sequence, open-label, two-way crossover bioequivalence study of two formulations of valsartan 160-mg tablets in healthy volunteers under fasting conditions

BACKGROUND Valsartan is a nonpeptide, orally active angiotensin II type 1 receptor blocker used to treat hypertension alone or in combination with other antihypertensive agents. OBJECTIVE The aim of this study was to compare the relative bioavailability of a new valsartan 160-mg formulation (ie, test drug) and that of a reference formulation so that bioequivalence could be assessed, as required by European regulatory authorities for the marketing of a generic product. METHODS This was a single-center, single-dose, randomized-sequence, open-label, 2-way crossover study with a minimum washout period of 7 days; drug was administered to healthy volunteers under fasting conditions. Blood samples were collected up to 36 hours postadministration, and valsartan levels were gauged from plasma by reverse liquid chromatography and tandem mass spectrometry detection (ie, the LC-MS/MS method). Pharmacokinetic parameters were calculated from valsartan concentration data using noncompartmental analysis. AUC(last), AUC(infinity), and C(max) were analyzed. The 90% CIs of the ratios of the test-versus-reference pharmacokinetic parameters (AUC(last), AUC(infinity), and C(max)) were obtained by ANOVA on ln-transformed data. The 90% CIs were required to be within 80.00% to 125.00% of the 90% CI to meet the criteria for bioequivalence. Tolerability was monitored using physical examination (including vital-sign measurements) and ECG performed at screening, as well as laboratory analysis, including biochemistry tests, hematology tests, and urinalysis, which were performed at screening and during the study period. RESULTS Thirty-eight white (90.5%), 2 black (4.8%), and 2 Hispanic subjects (4.8%) enrolled in the study; the sample included a total of 27 men and 15 women. The mean (SD) age was 37 (11) years and mean weight was 65.4 (7.6) kg. The 90% CI values for pharmacokinetic measurements were as follows: AUC(last), 94.45% to 118.59%; AUC(infinity), 93.58% to 116.51%; and C(max), 93.61% to 122.02%. Thus, they were all within the predefined 80.00% to 125.00% range. Thirty-six postadministration adverse events were reported; the most common was blood pressure decrease. A decrease of blood pressure was experienced by 6 subjects (14.6%) after the administration of the test formulation, and by 5 subjects (12.5%) after the administration of the reference formulation. Thirty-three of these adverse events were graded as mild and 3 as moderate; 11 were judged as probably related, 12 as possibly related, 3 as remotely related, and 10 as unrelated to the study medication. CONCLUSIONS In this open-label study of healthy volunteers, the test and reference formulations of valsartan 160 mg met the European regulatory definition of bioequivalence, based on the rate and extent of absorption of a single dose under fasting conditions. Both formulations were well tolerated.

Single-dose randomized, open-label, 2-way crossover bioequivalence study of clopidogrel 75 mg tablet in healthy volunteers under fasting conditions.

AIM This study aimed to assess the bioequivalence of 2 formulations of 75 mg clopidogrel hydrogen sulphate film-coated tablet, under fasting conditions. SUBJECTS AND METHODS 64 healthy subjects, age ranging from 19 to 55 years, were enrolled in a single-centre, randomized, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected up to 24 h post dosing. Clopidogrel and clopidogrel carboxylic acid levels were determined by reverse-phase high-performance chromatography coupled to tandem mass spectrometry detection, LC-MS-MS method. Pharmacokinetic parameters used for bioequivalence assessment were the AUClast (area under the concentration-time curve from time zero to time of last observed nonzero concentration) and the Cmax (maximum observed concentration). These parameters were determined from the clopidogrel concentration data using non-compartmental analysis as well for clopidogrel carboxylic acid concentration data. RESULTS The 90% CI (90% confidence intervals), obtained by analysis of variance (ANOVA) were within the predefined ranges (80.00 - 125.00%) for both analytes. CONCLUSION Bioequivalence between test and formulations, under fasting conditions, was concluded both in terms of rate and extent of absorption.

Bioequivalence study of two different film-coated tablet formulations of losartan-hydrochlorothiazide in healthy volunteers.

The study was conducted in order to assess the bioequivalence of two film-coated formulations containing 100 mg of losartan (CAS 124750-99-8) and 12.5 mg of hydrochlorothiazide (CAS 58-93-5). Seventy-three healthy subjects were enrolled in a randomised, single-dose, open-label, two-way crossover study, with a minimum washout period of 7 days. A total of 21 blood samples were collected up to 36 h post-dosing. Losartan, losartan carboxy acid and hydrochlorothiazide levels were determined by liquid chromatography with tandem mass detection (lower limit of quantification: 1.01 ng/mL for hydrochlorothiazide, 2.02 ng/mL for losartan and 2.51 ng/mL for losartan carboxy acid). Pharmacokinetic parameters used for bioequivalence assessment (AUC(0-t) and Cmax as primary and AUC(0-inf) as secondary pharmacokinetic parameters) were determined from the losartan and hydrochlorothiazide concentration data using non-compartmental analysis. Data from losartan carboxy acid was reported and presented as supportive data. The 90% confidence intervals (obtained by ANOVA) for losartan were 97.05-118.48% for Cmax 100.76-106.10% for AUC(0-t) and 100.80-106.10% for AUC(0-inf) whereas for hydrochlorothiazide the 90% confidence intervals obtained were 103.94-115.33% for Cmax, 101.97-109.61% for AUC(0-t) and 101.77-109.02% for AUC(0-inf), and for losartan carboxy acid the intervals obtained were 98.31-107.82% for Cmax, 97.89-104.30% for AUC(0-t) and 98.06-104.30% for AUC(0-inf). All the 90% confidence intervals obtained for all the parameters assessed were within the predefined ranges (80-125%). Based on these results, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.

Bioequivalence study of two different tablet formulations of donepezil using truncated areas under the curve. A single-center, single-dose, randomized, open-label, 2-way crossover study under fasting conditions.

BACKGROUND Donepezil hydrochloride (CAS 120014-06-4) is a piperidine-based, reversible inhibitor of the enzyme acetylcholinesterase (AChE). It is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine (ACh) through reversible inhibition of its hydrolysis by AChE. OBJECTIVE The aim of this study was to assess the bioequivalence of a new donepezil 10 mg formulation (test formulation) vs. the reference product, as required by European regulatory authorities for the marketing of a generic product. Additionally, the applicability of the truncated area under the plasma concentration curve (AUC) approach to this drug and under these test conditions was determined. METHODS This was a single center, randomized, single-dose, open-label, 2-way crossover study in healthy volunteers under fasting conditions. Plasma samples were collected up to 288 h post-dosing and (+)-donepezil and (-)-donepezil plasma levels were determined by reverse liquid chromatography and by tandem mass spectrometry detection (ie, the LCMS/MS method). Pharmacokinetic parameters were calculated using non-compartmental analysis. Area under the concentration-time curve from time zero to the time of the last non-zero concentration (AUC(last)) and maximum observed concentration (C(max)) were the main evaluation criteria, while area under the concentration-time curve from time zero to infinity (AUC(inf)) was also analyzed for additional information. For the assessment of the applicability of the truncated AUC approach, AUCs truncated at 24, 48, 72, 96, 144, 192, 240, and 288 h were calculated. All of the abovementioned pharmacokinetic parameters were analyzed using 90% geometric confidence interval of the ratio (T/R) of least-squares means from the ANOVA of the In-transformed parameter. Tolerability was monitored using physical examination, including vital sign measurements and laboratory analysis. RESULTS According to the classical approach, the 90% geometric confidence intervals obtained by analysis of variance for AUC(last), C(max) and AUC(inf) were within the predefined ranges (80.00-125.00%) for both analytes. Truncated AUCs were also in all cases within the predefined ranges for acceptance of bioequivalence. CONCLUSION Bioequivalence between test and reference formulations, both in terms of rate and extension of absorption, under fasting conditions, was concluded according to European guidelines. Both formulations were well tolerated. The conclusion of bioequivalence was also supported using the truncated AUCs approach.

Bioequivalence study of two enteric-coated formulations of pantoprazole in healthy volunteers under fed conditions.

This study was conducted in order to assess the bioequivalence of two enteric-coated formulations of 40 mg pantoprazole (CAS 102625-70-7), under fed conditions. Seventy-four healthy subjects, age ranging from 24 to 55 years, were enrolled in a two-centre, randomised, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected up to 30.0 h post-dosing. Pantoprazole levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection (LC-MS/ MS). Pharmacokinetic parameters used for bioequivalence assessment were the AUClast (area under the concentration-time curve from time zero to time of last observed non-zero concentration), AUCinf (area under the concentration-time curve from time zero to infinity) and Cmax, (maximum observed concentration). These parameters were determined from the pantoprazole concentration data using non-compartmental analysis. Gender-related differences were found in the variability of all relevant pharmacokinetic parameters. The 90% CI (90% confidence intervals), obtained by analysis of variance (ANOVA) were within the predefined ranges. Bioequivalence between the test and reference formulation, under fed conditions, was concluded both in terms of rate and extent of absorption.

Truncated areas under the curve in the assessment of pioglitazone bioequivalence: Data from a single-center, single-dose, randomized, open-label, 2-way cross-over bioequivalence study of two formulations of pioglitazone 45 mg tablets under fasting conditions

BACKGROUND Pioglitazone (CAS 112529-15-4 for the HCl form) is an oral antidiabetic agent that is a member of the group of drugs known as thiazolidinediones. It is indicated for the treatment of type 2 diabetes mellitus. OBJECTIVE The aim of this study was to assess the bioequivalence of a new pioglitazone 45 mg formulation (test formulation) vs. the reference product, as required by European regulatory authorities for the marketing of a generic product. Additionally, the applicability of the truncated area under the plasma concentration curve (AUC) approach to this drug and under these test conditions was determined. METHODS This was a single-center, randomized, single-dose, open-label, 2-way crossover study in healthy volunteers under fasting conditions. Plasma samples were collected up to 120 h post-dosing. Pioglitazone and hydroxypioglitazone plasma levels were determined by reverse liquid chromatography and by tandem mass spectrometry detection (LC-MS/MS). Pharmacokinetic parameters were calculated using non-compartmental analysis. Area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(last)) and maximum observed concentration (C(max)) were the main evaluation criteria, while the area under the concentration-time curve from time zero to infinity (AUC(inf)) was also analyzed for additional information. For the assessment of the applicability of the truncated AUC approach, AUCs truncated at 24, 48, 72, 96, and 120 h were calculated. All of the abovementioned pharmacokinetic parameters were analyzed using 90% geometric confidence interval of the ratio (T/R) of least-squares means from the ANOVA of the In-transformed parameter. Tolerability was monitored using physical examination, including vital sign measurements and laboratory analysis. RESULTS According to the classical approach, the 90% geometric confidence intervals obtained by ANOVA for AUC(last), C(max) and AUC(inf) were within the predefined ranges (80-125%) for both analytes. Truncated AUCs were also in all cases within the predefined ranges for acceptance of bioequivalence (e.g. 90% confidence interval). CONCLUSION Bioequivalence between test and reference formulations, both in terms of rate and extension of absorption, under fasting conditions was concluded according to European guidelines. Both formulations were well tolerated. The conclusion of bioequivalence was also supported using the truncated AUCs approach.

Study on the bioequivalence of two formulations of eplerenone in healthy volunteers under fasting conditions: data from a single-center, randomized, single-dose, open-label, 2-way crossover bioequivalence study.

BACKGROUND Eplerenone (CAS 107724-20-9) prevents the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone-system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular disease and is indicated, in addition to standard therapy including beta-blockers, to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (LVEF < or = 40%) and clinical evidence of heart failure after recent myocardial infarction. OBJECTIVE The aim of this study was to assess the bioequivalence of a new eplerenone 50 mg formulation (test formulation) vs. the reference product, as required by European regulatory authorities for the marketing of a generic product. METHODS This was a single-center, randomized, single-dose, open-label, 2-way crossover study in healthy volunteers under fasting conditions. Plasma samples were collected up to 24 h post-dosing and plasma eplerenone levels were determined by reversed phase high performance liquid chromatography and by tandem mass spectrometry detection (ie, the LC-MS/MS method). Pharmacokinetic parameters were calculated using non-compartmental analysis. Area under the concentration-time curve from time zero to time of last non-zero concentration (AUClast) and maximum observed concentration (Cmax) were the main evaluation criteria. All of the above-mentioned pharmacokinetic parameters were analyzed using 90% geometric confidence interval of the ratio (T/R) of least-squares means from the ANOVA of the 1n-transformed parameter. Tolerability was monitored using physical examination, including vital sign measurements and laboratory analysis. RESULTS According to the classical approach, the 90% geometric confidence intervals obtained by analysis of variance for AUClast and Cmax were within the predefined ranges (80.00-125.00%). CONCLUSION Bioequivalence between test and reference formulations, both in terms of rate and extension of absorption, under fasting conditions was concluded according to European guidelines. Both formulations were well tolerated.

Bioequivalence studies for two different strengths of montelukast in healthy volunteers: 10 mg film-coated tablets and 5 mg chewable tablets.

In order to assess the bioequivalence of 2 different formulations of montelukast, a pivotal trial for the montelukast 10 mg film-coated tablets formulation and a pivotal trial for the montelukast 5 mg chewable tablets formulation were conducted.For the 10 mg study, 34 healthy subjects were enrolled in a single centre, randomised, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days, while for the 5 mg study, 42 healthy subjects were included in another study with a similar design. For both studies, plasma samples were collected up to 24 h post-dosing and drug levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection.Pharmacokinetic parameters used for bioequivalence assessment, area under the concentration-time curve from time zero to time of last non-zero concentration (AUC0-t) and from time zero to infinity (AUC0-inf) and maximum observed concentration (Cmax), were determined from the drug concentration data using non-compartmental analysis.In the 10 mg study, the 90% confidence intervals obtained by analysis of variance were 99.62-120.51% for Cmax, 102.25-117.37% for AUC0-t and 101.96-116.67% for AUC0-inf, which were within the predefined acceptable range of 80.00-125.00%.In the 5 mg study, the 90% confidence intervals were 91.14-98.46% for Cmax, 93.02-98.42% for AUC0-t and 93.09-98.63% for AUC0-inf, which were within the predefined acceptable range of 80.00-125.00%.Bioequivalence between formulations was concluded both in terms of rate and extent of absorption for both strengths.

Comparative bioavailability of two formulations of sibutramine.

This study was conducted in order to compare the bioavailability of two capsule formulations containing 15 mg of sibutramine, N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine hydrochloride monohydrate, 84485-00-7 CAS registry number. 62 healthy subjects were enrolled in a single-center, randomized, single-dose, open-label, 2-way crossover study, with a minimum washout period of 14 days. Plasma samples were collected up to 72.0 hours post-dosing. R-sibutramine, S-sibutramine, N-mono-desmethyl-sibutramine (M1) and N-di-desmethyl-sibutramine (M2) levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection, LC/MS/MS method. Pharmacokinetic parameters used for bioequivalence assessment were the area under the concentration-time curve from time zero to time of last non-zero concentration (AUC0-t) and the maximum observed concentration (Cmax). These parameters were determined from sibutramine enantiomers as well from M1 and M2 concentration data using non-compartmental analysis. The 90% confidence intervals obtained by analysis of variance were 89.25 - 122.88% for Cmax, 90.37 - 123.18% for AUC0-t and 91.20 - 122.38% for AUCinf for R-sibutramine and 88.27 - 124.08% for Cmax, 86.15 - 121.78% for AUC0-t and 88.02 - 120.96% for AUCinf for S-sibutramine. These results were all within the range of 80.00 - 125.00% established by regulatory requirements. Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.

Bioequivalence of two formulations of levetiracetam.

This study was conducted in order to compare the bioavailability of two tablet formulations containing 1,000 mg levetiracetam, (S)-a-ethyl-2-oxo-1-pyrrolidine acetamide, 102767-28-2 CAS registry number. 18 healthy subjects were enrolled in a single-center, randomized, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected up to 36.0 hours post-dosing. Levetiracetam levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection, LC-MS/MS method. Pharmacokinetic parameters used for bioequivalence assessment, area under the concentration-time curve from time 0 to time of last non-zero concentration (AUClast) and from time zero to infinitive (AUCinf) and maximum observed concentration (Cmax), were determined from the levetiracetam concentration data using non-compartmental analysis. The 90% confidence intervals obtained by analysis of variance were 88.98 - 108.75% for Cmax, 99.90 - 104.81% for AUClast and 100.11 - 105.23 %for AUCinf this is, within the predefined ranges. Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.