Pharmacokinetic analysis and bioequivalence of Finasteride and Doxazosin formulated in a single tablet in comparison with the corresponding single agents

The most commonly agents used to treat benign prostatic hyperplasia (BPH) in clinical practice are finasteride and doxazosin employed alone or in combination. Randomized clinical trials have shown that combination therapy with finasteride and doxazosin is superior to finasteride alone or placebo. However, decreased patient compliance may lead to unsatisfactorily therapeutic results. The aim of this study was to assess whether the combined pharmacokinetic profile for both finasteride and doxazosin was not significantly altered when these agents were co-administered, in comparison with their use as single agents. This was a randomized 6 sequences and 3 periods, crossover, comparative study of three medications: finasteride (5 mg), doxazosin (2 mg) (references), and the fixed combination containing 5 mg of finasteride and 2 mg of doxazosin in a single tablet (test). Plasma samples obtained from 30 eligible subjects were analyzed simultaneously for finasteride and doxazosin by HPLC coupled to a LC-MS/MS having cyproterone acetate and terazosin as internal standards. The statistical analysis showed no significant differences for AUC0-72h (finasteride: 245.3±87.8 vs. test: 240.5±93.1 and doxazosin: 183.0±42.9 vs. test: 188.8±45.6 ng.h.mL-1), AUC0-∞ (finasteride: 247.4±92.1 vs. test:  40.47±93.1 and doxazosin: 190.3±44.3 vs. test: 188.8±45.6 ng.h.mL-1), and Cmax (finasteride: 34.2±7.1 vs. test: 29.9±6.2 and doxazosin: 16.3±3.6 vs. test: 14.9±3.3 ng/mL). The mean ratios of AUC0-72h/AUC0-∞ for finasteride and doxazosin were 99.99% and 99.98%, respectively, indicating that the sampling time was adequate for both drugs. In summary, the current pharmacokinetic study demonstrated bioequivalence between the single agents and the corresponding agents in combination and provided further evidence for the lack of pharmacokinetic interaction between finasteride and doxazosin

Bioequivalência de duas formulações de Valsartana 320mg comprimido revestido em participantes sadios de ambos os sexos em condição de jejum

Este estudo de bioequivalência foi realizado submetendo-se o medicamento teste valsartana comprimido revestido de 320 mg, produzido pela Eurofarma, e o medicamento referência, Diovan®, comprimido revestido de 320 mg, fabricado pela Novartis Biociências SA, a estudo de bioequivalência com a finalidade de comprovar a intercambialidade entre ambos. OBJETIVO: Estabelecer a bioequivalência e consequentemente a intercambiabilidade entre duas formulações de valsartana 320mg a partir de análise ANOVA. MÉTODOS: Foi realizado um estudo aleatorizado, aberto, cruzado, 2x2, com formulações contendo 320mg de valsartana em comprimido revestido, em participantes de ambos os gêneros, adultos, saudáveis, em condições de jejum. Foram selecionados e incluídos 60 participantes de pesquisa. Os participantes receberam, em cada um dos períodos de internação, 01 (um) comprimido revestido contendo 320 mg de valsartana, administrado por via oral em esquema de dose única, com 200 mL de água a temperatura ambiente. Foram coletadas amostras de sangue até 48h para determinação plasmática da valsartana. Para quantificação da droga, foi utilizada técnica de Cromatografia Líquida de Alta Eficiência acoplada à Espectrometria de Massas (LC-MS/MS). RESULTADOS: Foram obtidos os parâmetros farmacocinéticos concentração máxima (Cmax), área sob a curva de zero a 48h (ASC0-t) e área sob a curva de zero ao infinito (ASC0-inf). A média geométrica entre as formulações teste e referência foram de 100,88%, (91,47% - 111,26%) para Cmax, 99,75% (91,95% - 108,21%) para ASC0-t, e 99,33% (91,78% - 107,50%) para ASC0-inf. CONCLUSÃO: A partir dos resultados obtidos e em conformidade com a legislação vigente, pode-se afirmar que as formulações são bioequivalentes, e, portanto, intercambiáveis tendo sido a bioequivalência média alcançada com o intervalo de confiança compreendido entre 80 e 125% (IC 90%)

Determination of phenobarbital in human plasma by a specific liquid chromatography method: application to a bioequivalence study

A liquid chromatography method was developed and validated for the determination of phenobarbital in human plasma using phenytoin as internal standard. The drugs were extracted from plasma by liquid-liquid extraction and separated isocratically on a C12 analytical column, maintained at 35 ºC, with water:acetonitrile:methanol (58.8:15.2:26, v/v/v) as mobile phase, run at a flow rate of 1.2 mL/min with detection at 205 nm. The method was linear in the range of 0.1-4 μg/mL (r²=0.9999) and demonstrated acceptable results for the precision, accuracy and stability studies. The method was successfully applied for the bioequivalence study of two tablet formulations (test and reference) of phenobarbital 100 mg after single oral dose administration to healthy human volunteers

Bioequivalence of zolpidem hemitartrate: new formulations of 5 mg SL, 10 mg and 12.5 mg XR and comparison of their bioavailabilities

Objective: To evaluate pharmaceutical bioequivalence between two formulations of 5 mg zolpidem hemitartrate sublingual and, 10 and 12.5 mg extended-release formulations tablets in healthy subjects under fasting and fed conditions. Methods: An open label, monocentric, randomized, 2 x 2 crossover study in 40 healthy adults under fasting conditions comparing two formulations of zolpidem 5mg sublingual tablets. Analyte concentrations in human plasma were determined using a validated liquid chromatography with a tandem mass spectrometer detector method (LC-MS/MS). The same design was utilized to evaluate the other formulations. Results: Statistical analysis has determined geometric mean of test / reference ratio, confidence intervals, and power of the test to the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞. The geometric mean ratio (90%CI) of the test drug/reference drug for zolpidem 5mg were 99.89 to 113.57% for Cmax, 97.15% to 108.40% for AUC0-t, and 97.22% to 108.13% for AUC0-∞. Power of the test was 99.35% for Cmax and 100% AUC0-t, and AUC0-∞. Conclusion: Both test and reference are bioequivalent for all formulations and, therefore, they are interchangeable, according to the Brazilian criteria (Anvisa resolution RE nº 1170/2006), since confidence intervals for Cmax and AUC0-t ratios were within 80% and 125%

Comparative pharmacokinetics study of a formulation of amlodipine + enalapril versus an enalapril maleate formulation in healthy volunteers of both genders

Orientador: Gilberto de NucciDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: Introdução: Com base em evidências de estudos mostrando que em cerca de 2/3 dos casos de hipertensão a monoterapia não é suficiente para atingir as reduções pressóricos previstas, e diante da necessidade de controle mais rigoroso dos níveis pressóricos, há clara tendência atual para a introdução precoce de terapêutica combinada de anti-hipertensivos como primeira medida farmacológica. Tais associações de anti-hipertensivos podem ser feitas por meio de fármacos em separado ou por associações em doses fixas. Entre as associações eficazes conhecidas tem-se o caso de inibidores de enzima conversora de angiotensina e bloqueadores dos canais de cácio; um exemplo desta associação é a de amlodipina e enalapril. Objetivo: O presente estudo analisa a farmacocinéica comparativa de um produto contendo Amlodipina e outro contendo enalapril com um produto contendo a combinação dos dois princípios ativos. O produto testado foi Sinergen® (5mg/20mg) dos Laboratórios Biosintética Ltda. O produto referência para o Amlodipina foi o Norvasc®, comprimido de 5 mg, produzido pelo Laboratório Pfizer Ltda e o produto referência para o Enalapril foi o Renitec®, comprimido de 20 mg, produzido pela Merck Sharp Dohme. Materiais e métodos: 36 voluntários saudáveis de ambos os sexos foram internados em três oportunidades, nas quais receberam a associação de amlodipina e enalapril, amlodipina individualmente e enalapril individualmente. Coletas a intervalos regulares foram durante 144 horas para amlodipina e durante 24 horas para enlapril. As concentrações de Amilodipina, Enalapril e Enalaprilato foram medidas através de método analítico apropriado e validado por espectrofotometria de massas (LC-MS MS). A análise estatística dos resultados foi realizada mediante ANOVA. Resultados: As razões teste/referência das formulações para os parâmetros Cmax e ASC em estudo estiveram dentro do intervalo de 80-125%. Conclusão: Após análise estatística correspondente por ANOVA, chegou-se à conclusão que a formulação teste Sinergen é bioequivalente no que diz respeito às formulações referência Renitec (Enalapril) e Novarsec (amlodipina), já que todas as relações T/R para Cmax, AUC 0-inf e AUC 0-last das formulações estavam compreendidas no intervalo 80%-125%, determinado por ANVISA como condição de bioequivalênciaAbstract: Introduction: Based on evidence of studies showing that in 2/3 of the cases of hypertension monotherapy is not enough to reach pressure reduction and facing the necessity of a more rigorous control, there is a clear current trend to the early introduction of a combined therapy of anti-hypertensive drugs as first pharmacological measure. These associations of anti-hypertensives can be made through separate products or through associations in fixed doses. Among the known efficient associations there is the case of angiotensin converting enzyme (ACE) inhibitors and calcium channels blockers; an example of these associations is the one of amlodipine and enalapril. Objective: This study analyses the comparative pharmacokinetics of a product containing amlodipine, a second one containing enalapril against a product containing the two active principles. The product test, Sinergenè (5mg/20mg) was manufactured by Laborat?ios Biosint?ica Ltda. The reference product for Amlodipina was Norvascè, 5 mg tablet, manufactured by Laborat?io Pfizer Ltda and the reference product for Enalapril was Renitecè, 20 mg tablet, manufactured by Merck Sharp Dohme. Materials and methods: 36 healthy volunteers of both genders were confined in three periods during which they received the association of amlodipina and enalapril, amlodipine individually and enalapril individually. Collects at regular intervals during 144 hours for amlodipine and 24 hours for enalapril were measured through a proper validated analytical method. The plasmatic concentrations of Amlodipine, Enalapril and enalaprilate were measured by a proper validated analytical method of mass spectrometry (LC-MS-MS). The statistical analysis was performed by ANOVA. Results: The relation of test and reference of the formulations for the parameters Cmax and AUC were within 80-125%. Conclusion: After statistical analysis by ANOVA, we reached the conclusion that the test formulation, Sinergen, is bioequivalent to the reference formulations Renitec (Enalapril) and Novarsec (amlodipina), since all the T/R relations for Cmax, AUC 0-inf and AUC 0-last of the formulations were within 80%-125% interval determined by ANVISA as condition of bioequivalenceMestradoMestre em Farmacologi

Bioequivalence study between two formulations of 10mg lenalidomide capsules in healthy male subjects under fasting conditions

OBJECTIVE: To evaluate pharmaceutical bioequivalence between two formulations of 10mg lenalidomide capsules in healthy male subjects under fasting conditions. MATERIAL AND METHODS: An open label, monocentric, randomized, 2x2 crossover study in 32 healthy men under fasting conditions comparing two formulations of lenalidomide capsules. Analyte concentrations in human plasma were determined using a validated liquid chromatography with a tandem mass spectrometer detector method (UPLC-MS/MS). RESULTS: Statistical analysis has determined geometric mean of test/reference ratio, confidence intervals, and power of the test to the pharmacokinetic parameters Cmax and AUC0-t as required by Anvisa resolution, the geometric mean ratio (90%CI) of the test drug/reference drug were 84.01 to 108.10 for Cmax and 98.58 to 105.34 for AUC0-t. Power of the test was 89.9% for Cmax and 100.0% for AUC0-t

Determination Of Chlorpheniramine In Human Plasma By Hplc-esi-ms/ms: Application To A Dexchlorpheniramine Comparative Bioavailability Study.

In the present study a fast, sensitive and robust validated method to quantify chlorpheniramine in human plasma using brompheniramine as internal standard (IS) is described. The analyte and the IS were extracted from plasma by LLE (diethyl ether-dichloromethane, 80:20, v/v) and analyzed by HPLC-ESI-MS/MS. Chromatographic separation was performed using a gradient of methanol from 35 to 90% with 2.5 mm NH(4)OH on a Gemini Phenomenex C(8) 5 microm column (50 x 4.6 mm i.d.) in 5.0 min/run. The method fitted to a linear calibration curve (0.05-10 ng/mL, R > 0.9991). The precision (%CV) and accuracy ranged, respectively: intra-batch from 1.5 to 6.8% and 99.1 to 106.6%, and inter-batch from 2.4 to 9.0%, and 99.9 to 103.1%. The validated bioanalytical procedure was used to assess the comparative bioavailability in healthy volunteers of two dexchlorpheniramine 2.0 mg tablet formulations (test dexchlorpheniramine, Eurofarma, and reference Celestamine, Schering-Plough). The study was conducted using an open, randomized, two-period crossover design with a 2 week washout interval. Since the 90% confidence interval for C(max) and AUC ratios were all within the 80-125% interval proposed by ANVISA and FDA, it was concluded that test and reference formulations are bioequivalent concerning the rate and the extent of absorption.24774-8

Determination of chlorpheniramine in human plasma by HPLC-ESI-MS/MS: application to a dexchlorpheniramine comparative bioavailability study

In the present study a fast, sensitive and robust validated method to quantify chlorpheniramine in human plasma using brompheniramine as internal standard (IS) is described. The analyte and the IS were extracted from plasma by LLE (diethyl ether-dichloromethane, 80:20, v/v) and analyzed by HPLC-ESI-MS/MS. Chromatographic separation was performed using a gradient of methanol from 35 to 90% with 2.5 mm NH(4)OH on a Gemini Phenomenex C(8) 5 mu m column (50 x 4.6 mm i.d.) in 5.0 min/run. The method fitted to a linear calibration curve (0.05-10 ng/mL, R > 0.9991). The precision (%CV) and accuracy ranged, respectively: intra-batch from 1.5 to 6.8% and 99.1 to 106.6%, and inter-batch from 2.4 to 9.0%, and 99.9 to 103.1%. The validated bioanalytical procedure was used to assess the comparative bioavailability in healthy volunteers of two dexchlorpheniramine 2.0 mg tablet formulations (test dexchlorpheniramine, Eurofarma, and reference Celestamine (R), Schering-Plough). The study was conducted using an open, randomized, two-period crossover design with a 2 week washout interval. Since the 90% confidence interval for C(max) and AUC ratios were all within the 80-125% interval proposed by ANVISA and FDA, it was concluded that test and reference formulations are bioequivalent concerning the rate and the extent of absorption. Copyright (C) 2009 John Wiley & Sons, Ltd