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%)

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%

Therapeutic drug monitoring of imatinib mesylate: relationship between serum levels and the molecular outcome (as determined by major molecular response) in chronic myeloid leukemia

Dentre os vários tipos de leucemia, destaca-se a Leucemia Mielóide Crônica (LMC), um distúrbio mieloproliferativo em que ocorre a translocação entre o gene BCR no cromossomo 22 e o gene ABL1 no cromossomo 9. Essa translocação cria um cromossomo conhecido como Philadelphia (t 9,22)(q34;q11), ou Ph+, e a consequente formação de um produto único de proteínas BCR-ABL1. Essa proteína tem atividade de quinase constitutiva e impulsiona a proliferação descontrolada de células tronco hematopoiéticas. O surgimento de uma nova classe farmacológica no início dos anos 2000 - os inibidores de tirosina quinases, revolucionou o tratamento e o prognóstico da LMC, permitindo que esse câncer fosse tratado praticamente como uma doença crônica, com farmacoterapia oral. A droga de estréia dessa classe, o Mesilato de Imatinib, foi desenvolvida através de modelagem molecular para ser alvo-específica, mas apesar do desenvolvimento exitoso, após o início da comercialização, foram observadas falhas na ação em determinados pacientes. Há evidências de que a avaliação da relação entre a dose de imatinibe (e seus níveis sanguíneos) e a eficácia do tratamento medida através das respostas Hematológica, Citogenética e Molecular, seja uma forma de realizar o ajuste da dose reduzindo efeitos colaterais e custo do tratamento. No presente estudo foram avaliadas as concentrações séricas de imatinib, Cmin e Cmax, em 51 pacientes com Leucemia Mielóide Crônica, dos quais 33 atingiram Resposta Molecular Maior em até 12 meses de tratamento, 11 levaram mais que 12 meses para antingir, e 7 não atingiram. As concentrações séricas obtidas desses pacientes indicaram que no grupo que atingiu RMM em até 12 meses, os valores de vale (Cmin) se apresentaram com mediana de 889.2 ng/mL (721.9 e 1202.4 para primeiro e terceiro quartis respectivamente), sendo que o grupo que levou mais de 12 meses para atingir RMM, a concentração mediana observada foi de 611.0 ng/mL (493.0 e 816.0 para primeiro e terceiro quartis respectivamente), sendo essa diferença estatisticamente significativa (p < 0.05). Dessa forma demonstrou-se a importância do monitoramento das concentrações séricas de imatinib para o ajuste da dose e para a gestão do tratamento na mudança para segunda geração de inibidores de tirosina quinase. Através da análise comparativa dos dados populacionais estudados, observou-se não haver correlação significativa entre as concentrações séricas e índice de massa corpórea (IMC), peso, idade ou sexoAmong the various types of leukemia, Chronic Myeloid Leukemia (CML) stands out as a myeloproliferative disorder in which translocation occurs between the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9. This translocation creates a chromosome known as Philadelphia (t 9,22) (q34; q11), or Ph +, and the consequent formation of a unique BCR-ABL1 protein product. This protein has constitutive kinase activity and drives the uncontrolled proliferation of hematopoietic stem cells. The launch of a new pharmacological class in the early 2000s - the tyrosine kinases inhibitors, revolutionized the treatment and prognosis of CML, allowing that cancer to be treated virtually as a chronic disease with oral pharmacotherapy. The newbie drug of this class, Imatinib Mesylate, was developed through molecular modeling to be target-specific, but despite the successful development, after the beginning of marketing, certain patients presented some failures in the response. There is an evidence that an assessment of the relationship between a dose of Imatinib (and its blood levels) and the efficacy of treatment from its Hematologic, Cytogenetic and Molecular Responses, is a really effective way to perform dose adjustment reducing side effects and cost of treatment. In the present study, the serum concentrations of Imatinib, Cmin and Cmax were evaluated in 51 patients with chronic myeloid leukemia, of which 33 reached major molecular response in up to 12 months of treatment, 10 took more than 12 months to achieve it, and 7 did not reach that. The serum concentrations obtained from those patients indicated that in the group that reached Major Molecular Response (MMR) within 12 months, the trough level (Cmin) presented a median of 889.2 ng / mL (721.9 and 1202.4 for first and third quartiles, respectively), and the group which took more than 12 months to reach MMR, the median concentration observed was 611.0 ng / mL (493.0 and 816.0 for the first and third quartiles respectively), and this difference was statistically significant (p < 0.05). Thus, the importance of monitoring serum imatinib concentrations for dose adjustment and treatment management in switching to second-generation tyrosine kinase inhibitors has been demonstrated. Through the comparative analysis of the population data, there was no significant correlation between serum concentrations and body mass index (BMI), weight, age or gende

Certification of beta-N-methyl-amino-alanine: a model for in-house preparation of reference materials of organic substances

Materiais de Referência (MR) de substâncias químicas têm ampla aplicação, sobretudo na área analítica, servindo de referência para validação de métodos, calibração de instrumentos e controle de qualidade, estabelecendo a comparabilidade de resultados analíticos em escala global e permitindo a transferência da exatidão entre métodos, laboratórios e padrões. Norteado por essas necessidades, o trabalho apresenta uma proposta para certificação de MR baseada nas orientações preconizadas por diretrizes e normas internacionais, principalmente as que seguem o ISO Guia 34, para estabelecer as propriedades certificadas através de técnicas analíticas de Espectrometria de Massas de Alta Resolução, Ressonância Magnética Nuclear, de ¹H e de ¹³C, e de Análise Elementar CHN. A certificação contemplou as caracterizações qualitativa e quantitativa, ensaio de estabilidade e o cálculo da estimativa da incerteza da medição. Como resultado, foi produzido e certificado um lote piloto de MR de &#946;-N-metilamino-alanina (BMAA), uma toxina obtida in-house através de síntese química e purificação, cujos valores de propriedades certificadas foram rastreáveis ao SI e acompanhadas da estimativa da incerteza da medição.Reference Materials (RM) of chemicals have wide application, particularly in the analyses, providing a reference for validation of methods, instrument calibration and quality control, establishing the comparability of analytical results on a global scale and enabling the transfer of accuracy between methods, laboratories and standards. Guided by these requirements, the paper presents a proposal for certification of MR based on the guidelines recommended by international guidelines and standards, especially those which follow the ISO Guide 34, to establish the certified properties through analytical techniques of mass spectrometry High resolution Nuclear Magnetic Resonance, ¹H and ¹³C, and CHN elemental analysis. The certification included qualitative and quantitative characterization, stability test and the calculation of the estimate of measurement uncertainty. As a result, was produced and certified a pilot batch of RM &#946;-N-methylamino-alanine (BMAA), a toxin obtained in-house via chemical synthesis and purification, whose property values are certified and traceable to the SI accompanied by an estimative of the uncertainty of measurement

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

Núcleos de Ensino da Unesp: artigos 2008

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq