Bioekvivalenční studie jsou ve farmaceutickém průmyslu velmi důležitou částí vývoje léčivého přípravku. Jejich podstatou je sledování farmakokinetických a farmakodynamických parametrů po podání testovaných přípravků (farmaceutických ekvivalentů nebo farmaceutických alternativ) s cílem hodnocení jejich terapeutické zaměnitelnosti. Význam bioekvivalenčních studií roste i vzhledem k velkému nárůstu výroby a spotřeby generických preparátů, které v současnosti v mnoha evropských zemích a v USA tvoří přibližně 50 % celkové preskripce. Výsledky bioekvivalenčních studií jsou spolu s údaji o farmaceutické kvalitě léčivého přípravku jednou z hlavních součástí registrační dokumentace předkládané výrobci generik národním regulačním autoritám. Registrace generických přípravků totiž nevyžaduje na rozdíl od přípravků originálních náročné a nákladné klinické zkoušení. Porovnání originálního přípravku a přípravku generického pomocí bioekvivalenčních studií je považováno za dostatečné. Cílem článku je poskytnout lékařské veřejnosti přehled o typech bioekvivalenčních studií, rozsahu a pravidlech pro jejich provádění, a umožnit tak získat svůj vlastní názor na terapeutickou zaměnitelnost léčivých přípravků.
Bioequivalence studies are very important for the development of a pharmaceutical preparation in the pharmaceutical industry. Their rationale is the monitoring of pharmacokinetic and pharmacodynamic parameters after the administration of tested drugs. The target of such study is to evaluate the therapeutic compatibility of tested drugs (pharmaceutical equivalents or pharmaceutical alternatives). The importance of bioequivalence studies is increasing also due to the large growth of the production and consumption of generic products. Generic products represent approximately 50 % of the whole consumption in many European countries and USA. The search output of bioequivalence study is together with the pharmaceutical quality data of medical product one of the main part of the registration file submitted to a national regulatory authorities. The registration of generic products does not demand complicated and expensive clinical study contrary to original product. The comparison of the original and the generic product via bioequivalence study is suggested as sufficient. The aim of this article is to provide to a medical public a summary about the types of bioequivalence studies, their range, rules of their practise and let them gain their own attitude to this question.
- MeSH
- European Union MeSH
- Drugs, Generic pharmacokinetics pharmacology MeSH
- Pharmaceutical Preparations analysis classification standards MeSH
- Humans MeSH
- Drug Approval methods legislation & jurisprudence MeSH
- Therapeutic Equivalency MeSH
- Check Tag
- Humans MeSH
- Publication type
- Guideline MeSH
- Geographicals
- Czech Republic MeSH
The governments of many countries strongly support the production and clinical use of generic medicinal products which are “copies” of patented drugs and can be marked at lower cost. At present time bioequivalence testing is regarded as a useful methodology to perform comparisons among different products containing the same active ingredient. This report presents the results of comparative bioequivalence study of three meloxicam formulations: brand-drug “Melbek” with tablets and capsules of meloxicam developed at the Tashkent Pharmaceutical Institute. The results obtained confirm the bioequivalence of the studied drugs, which indicate about scientifically based approach to the selection of excipients and technological process in the development of the above generic drugs.
- MeSH
- Anti-Inflammatory Agents, Non-Steroidal * pharmacokinetics MeSH
- Drugs, Generic * pharmacokinetics MeSH
- Dosage Forms MeSH
- Humans MeSH
- Therapeutic Equivalency MeSH
- Check Tag
- Humans MeSH
- Publication type
- Comparative Study MeSH
The in vitro steady state fluxes (8-48h) of acyclovir were measured using full-thickness excised human skin to compare the transdermal permeation of the drug from two commercial topical preparations Herpesin cream and Zovirax cream. The variable, BR (bioavailability ratio), characterizing the mean ratio of the transdermal fluxes of acyclovir from Herpesin cream to the fluxes fi-om Zovirax cream, was BR = 1,1 ± 0,16, and confirms the topical bioequivalence ofthe preparations tested.
BACKGROUND: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations. RESEARCH DESIGN AND METHODS: The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC0-72h, AUC0-∝, Cmax, Tmax, T1/2 and Kel. RESULTS: The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for Cmax, the 90% CI for this parameter for itraconazole was 93.49-133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15-138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events. CONCLUSIONS: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.
- MeSH
- Antifungal Agents administration & dosage pharmacokinetics MeSH
- Administration, Oral MeSH
- Adult MeSH
- Itraconazole administration & dosage analogs & derivatives pharmacokinetics MeSH
- Cross-Over Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Area Under Curve MeSH
- Half-Life MeSH
- Therapeutic Equivalency MeSH
- Capsules MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
AIM: A randomized, two-way, crossover, bioequivalence study was conducted in 25 fasting, healthy, male volunteers to compare two brands of fexofenadine 180 mg tablets, FEXOFENADINE 180 mg Film Tablet (Drogsan A.S., Ankara, Turkey) as test and Telfast 180 mg Tablet (Aventis Pharma, Frankfurt am Main, Germany) as a reference product. METHOD: One tablet of either formulation was administered after 10 h of overnight fasting. After dosing, serial blood samples were collected during a period of 48 hours. Plasma samples were analysed for fexofenadine by a validated HPLC method. The pharmacokinetic parameters AUC(0-48), AUC(0-alpha), C(max), T(max), K(el), T(1/2), and CL were determined from plasma concentration-time profiles for both formulations and were compared statistically. RESULTS AND CONCLUSIONS: The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range, satisfying the bioequivalence criteria of the FDA. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles and that Drogsan's Fexofenadine is equivalent to Telfast of Aventis Pharma, Frankfurt am Main, Germany.
- MeSH
- Anti-Allergic Agents administration & dosage pharmacokinetics MeSH
- Administration, Oral MeSH
- Adult MeSH
- Cross-Over Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Histamine H1 Antagonists, Non-Sedating administration & dosage pharmacokinetics MeSH
- Tablets MeSH
- Therapeutic Equivalency MeSH
- Terfenadine administration & dosage analogs & derivatives pharmacology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
AIMS: To demonstrate the bioequivalence of macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of macitentan and tadalafil in healthy subjects. METHODS: Studies AC-077-101 and AC-077-103 were single-centre, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods. RESULTS: Bioequivalence of macitentan, its active metabolite ACT-132577, and tadalafil was established for FDC-2 in both studies AC-077-101 and AC-077-103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration-time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000-1.2500). No subject died and no serious adverse events were reported in either studies. CONCLUSION: The FDC-2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination.
- MeSH
- Adult MeSH
- Drug Combinations MeSH
- Hypoglycemic Agents * pharmacology MeSH
- Cross-Over Studies MeSH
- Delayed-Action Preparations MeSH
- Middle Aged MeSH
- Humans MeSH
- Metformin * MeSH
- Adolescent MeSH
- Young Adult MeSH
- Area Under Curve MeSH
- Pyrimidines * pharmacology MeSH
- Sulfonamides * pharmacology MeSH
- Tablets MeSH
- Tadalafil * pharmacology MeSH
- Therapeutic Equivalency MeSH
- Healthy Volunteers MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
A randomized, two-way, crossover, bioequivalence study was conducted in 26 fasting, healthy, male volunteers to compare two brands of citalopram 40 mg tablets, Citol (Abdi Ibrahim Ilaç San. ve Tic A.S., Istanbul, Turkey) as a test and Cipramil (H. Lundbeck A/S, Copenhagen, Denmark) as a reference product. One tablet of either formulation was administered with low-carbonate water after 10 h of overnight fasting. After dosing, serial blood samples were collected during a period of 24 hours. Plasma samples were analysed for citalopram by a validated HPLC method. The pharmacokinetic parameters AUC0-24, AUC(0-alpha), Cmax, Tmax, K(el), T(1/2), and CL were determined from plasma concentration-time profiles for both formulations and were compared statistically to evaluate bioequivalence between the two brands of citalopram, using the statistical modules recommended by FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles and that Abdi Ibrahim's Citol is equivalent to Cipramil of H. Lundbeck, Copenhagen, Denmark.
- MeSH
- Administration, Oral MeSH
- Citalopram administration & dosage pharmacokinetics MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Selective Serotonin Reuptake Inhibitors administration & dosage pharmacokinetics MeSH
- Therapeutic Equivalency MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
BACKGROUND: A new oral paracetamol formulation with the same paracetamol quantity (24 mg/mL) as a marketed formulation but with finer active ingredient particle size and lower amounts of maltitol (5.85 g/dose in the test formulation vs 7.25 g/dose in the reference formulation) and sorbitol (2.4 g/dose vs 2.83 g/dose) was developed. OBJECTIVE: Establish the bioequivalence of the new pediatric formulation (test treatment) compared with the marketed formulation (reference treatment). METHODS: This Phase I, open-label trial assigned healthy adult volunteers to a single 42-mL (1 g para-cetamol) dose of test or reference treatment. Participants received both treatments in a randomized order separated by a 72-hour washout period. The primary endpoints were AUC0-tlast (AUC vs time curve from time 0 to last measurable sampling timepoint), Cmax, and tmax. Safety assessments included adverse event, clinical laboratory, and physical examination data. RESULTS: Thirty-five participants were randomized and treated. The study population was 42.9% women (57.1% men) with a median age of 30 years; most participants were non-Hispanic White. Mean Cmax values were comparable between test and reference products, with a median tmax of 1.00 hour for both. The test/reference ratios (%) (90% CI) for AUC0-tlast and Cmax were 98.69% (96.46, 100.97) and 100.73% (95.63, 106.10), respectively. There were no adverse events or deaths. CONCLUSIONS: The new paracetamol formulation is bioequivalent to the marketed formulation.
- Publication type
- Journal Article MeSH
The purpose of this work was to develop a new supergeneric product Meloxicam/Omeprazole. Such a combination brings a benefit in terms of decreasing side effects for the patients using meloxicam. The new combination is composed of a meloxicam powder blend (MPB) and omeprazole gastro-resistant pellets (OAP) in hard gelatin capsules. The main tasks were to select the excipients to keep the functional layer of OAP active and to prove the bioequivalence to the original products of meloxicam tablets together with omeprazole capsules. Although dissolution profiles similar to the original product were obtained, the unexpected results of omeprazole low bioavailability in the fed bioequivalence study (BES I) showed the necessity to investigate the formulation in greater depth. A modified more complex dissolution method was developed in order to understand the release of omeprazole under gastric conditions. This method revealed the degradation of omeprazole in the formulation when exposed to the fed conditions because of the increase in microenvironmental pH in the capsule caused by trisodium citrate, commonly used for improving solubility of meloxicam. This pH increase dissolved the gastro-resistant layer of OAP and caused the chemical degradation. To prevent this effect, a trisodium citrate-free formulation was developed. Reformulated capsules passed the repeated fed bioequivalence study (BES II).
- MeSH
- Anti-Inflammatory Agents, Non-Steroidal * administration & dosage chemistry pharmacokinetics MeSH
- Citrates chemistry MeSH
- Chemistry, Pharmaceutical MeSH
- Drug Combinations MeSH
- Cross-Over Studies MeSH
- Hydrogen-Ion Concentration MeSH
- Humans MeSH
- Meloxicam MeSH
- Omeprazole * administration & dosage chemistry pharmacokinetics MeSH
- Excipients chemistry MeSH
- Powders MeSH
- Anti-Ulcer Agents * administration & dosage chemistry pharmacokinetics MeSH
- Therapeutic Equivalency MeSH
- Thiazines * administration & dosage chemistry pharmacokinetics MeSH
- Thiazoles * administration & dosage chemistry pharmacokinetics MeSH
- Capsules MeSH
- Drug Liberation MeSH
- Gelatin chemistry MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial MeSH
