Class of 2006 Abstract / Background: Approximately 2% of the population has hypothyroidism, and are treated with a levothyroxine product. Unlike other medications, levothyroxine products have not been considered substitutable due to their narrow therapeutic window. Objectives: To compare the bioequivalence study findings from studies conducted by the manufacturer of Synthroid to those conducted by other investigators. Methods: Studies comparing levothyroxine product bioequivalence were found and divided according to time period, study design, and major funding party. Results: Ten studies excluded due to a change in Synthroid formulation. Six steady state studies and 3 single dose studies were left. Conclusions: Although data suggests bioequivalence between all studied levothyroxine products, there was not enough data to make a conclusion.

A avaliação biofarmacêutica de formas farmacêuticas contendo ampicilina foi realizada em dois lotes de cápsulas e dois de suspensão oral. O estudo da bioequivalência seguiu delineamento experimental cruzado, com dois períodos, empregando 16 voluntários de ambos os sexos (7 homens e 9 mulheres), com idades entre 21 e 26 anos (média de 23 anos) e peso entre 48 e 105 Kg (média de 68,2 Kg), dentro do intervalo de 10 % do peso ideal. Exames clínicos e laboratoriais foram realizados para selecionar os voluntários, sendo excluídos aqueles que apresentaram alguma alteração nos parâmetros clínicos normais ou com histório de reação alérgica às penicilinas e, ainda, os indivíduos que estivessem fazendo uso de medicamentos a menos de uma semana da realização do estudo. O protocolo experimental foi aprovado previamente pela Comissão de Ética do Hospital Universitário (HUUSP). Os ensaios de bioequivalência foram efetuados em períodos distintos para cada forma farmacêutica, com uma semana de intervalo. No dia dos testes e após jejum de 12 horas, os voluntários foram divididos em dois grupos com igual número de indivíduos, sendo que, a cada grupo foi administrada dose única de 500 mg de ampicilina de lotes diferentes. Após período de wash out de 48 horas, a administração dos produtos aos grupos foi invertida para que todos os indivíduos recebessem ambos os produtos. A determinação quantitativa da ampicilina foi realizada em amostras de urina coletadas num período de doze horas, aplicando o método espectrofotométrico, com leituras a 320 nrn, após reação a 70° C em solução tampão fosfato/sulfato de cobre por 30 minutos. Os parâmetros farmacocinéticos calculados foram: quantidade acumulada de ampicilina na urina (Xuacumul), velocidade máxima de excreção urinária (Vmáx), tempo no qual essa velocidade foi atingida (tmáx), constantes de velocidade de eliminação (K) e de excreção urinária (ku)e a meia-vida de eliminação (t1/2). A recuperação de ampicilina inalterada na urina variou de 54,5 a 58,9 % e de 54,6 a 57,8 % das doses administradas para cápsulas e suspensão, respectivamente; a meia-vida média calculada foi de 1,9 h para cápsulas e de 1,7 h para suspensão. Os intervalos de confiança (α= 0,10) calculados para a razão das médias das quantidades acumuladas de ampicilina estão contidos no limite de 80 a120 %. A análise estatística dos resultados aplicando métodos paramétrico (ANOVA) e não paramétrico (Mann-Whitney), conforme as normas preconizadas pelo FDA, comprovou que não há diferenças significativas (nível de significância de 90 %) entre os produtos A e B quanto aos parâmetros estudados. / A biopharmaceutic quality evaluation of two brands of ampicillin capsule and suspension dosage forms is presented. The bioequivalence study was based on an open randomized two-period crossover design with 7 male and 9 female healthy volunteers, aged 21 to 26 years (mean 23 yr) with body weights ranging from 48 to 105 Kg (mean 68,2 Kg) and within 10 % of the ideal body weight. All subjects passed by routine clinical and laboratory examinations. The volunteers had no histories of alergic reaction to penicillins and no other drugs were taken for at least 1 week before starting the study. The clinical protocol was approved by the Ethics Committee ofthe University Hospital (HUUSP). Studies were conducted separately for each dosage form after 1 week interval. On the day of the study, following an overnight fast, subjects were divided into two groups, each receiving 500 mg single dose of one of the two ampicillin dosage form. After a 2-day washout period, the same products were given in inversed order. Ampicillin data were obtained from urine samples collected over a 12 hour period. A spectrophotometric measurement at 320 nm after reaction in copper-phosphate/sulfate buffer solution at 70°C for 30 minutes was used. Total cummulative urinary excretion (Xuacumul), urinary excretion rates (Vmax), time to peak (tmax), urinary excretion rate constants (ku), elimination rate constants (K), and elimination half lives (t1/22) were calculated. Mean urine unchanged ampicillin recoveries of administered doses ranged from 54,5 to 58,9 % for capsules and from 54,6 to 57,8% for suspensions; t1/2 ranged from 1,7 to 1,9 h. Confidence intervals (α=0,10) for average rates were within 80-120 %. Statistic parametric (ANOVA) analysis and non-parametric analysis (Mann-Whitney) showed non-significance differences on the studied parameters of the two products at 90% significance leveI, according to FDA regulations.

Orientador: Ronilson Agnaldo Moreno / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-05T05:47:22Z (GMT). No. of bitstreams: 1 Maluly_HellenDeaBarros_M.pdf: 7988282 bytes, checksum: 2d5724c0002bc95aaec9c7de5cbd35bd (MD5) Previous issue date: 2005 / Resumo: O Objetivo deste estudo foi comparar a bioequivalência do Cefadroxil - cápsula (500mg) da Apotex do Brasil Ltda (formulação teste) and Cemmox@do Laboratório Bristol-Myers Squibb (formulação de referencia) em voluntários sadios de ambos os sexos. Este estudo foi necessário para comercialização deste medicamento. O estudo foi aleatorizado, cruzado, com dois períodos e duas seqüências (2x2) e com uma semana de intervalo entre as doses (wash out), onde os mesmos voluntários receberam, em cada período a formulação teste e a formulação de referência. A seqüência de tratamento foi determinada por uma lista de aleatorização, automaticamente produzida pela Medicines Clinical Trials Control System. As amostras de plasma foram coletadas num intervalo de 36 horas. As concentrações de Cefadroxil foram analisadas por cromatografia líquida de alta eficiência acoplada a um detector de UV-visível. A partir da curva da concentração de Cefadroxil no plasma vs tempo foram obtidos os parâmetros farmacocinéticos: 'ASC IND. 0-t¿, 'ASC IND. 0-INFINITO¿ e 'C IND. max¿. As médias geométricas de CefadroxiI / 'Cefamox MARCA REGISTRADA¿ 500 mg em porcentagem foram: 105.58% (90% CI=102.17%; 109.10%) para 'ASC IND. 0-t¿, 104.74% (90% CI= 101.55%; 108.02%), para 'ASC IND. 0-INFINITO¿ 112.08% (90% CI=10S.59%; 118.97%) para 'C IND. max¿.Sendo 90% o intervalo de confiança para 'C IND. max¿, 'ASC IND. 0-t¿, 'ASC IND. 0-INFINITO¿ estiverem entre 80-125% do intervalo proposto pela RDC 135 (ANVISA/mai 2003), conclui-se que o Cefadroxil - cápsulas (500 mg) foi bioequivalente ao Cefamox MARCA REGISTRADA¿ ,de acordo com as porcentagens e extensão da absorção / Abstract: The objective of this study is to compare the bioequivalence of Cefadroxil- capsule 500 mg ¿ formulated by Apotex of Brazil Ltda (test formulation) and Cefamox by LaboratoryBristol-Myers Squibb (reference formulation) in volunteers of both sexes. This study was necessary for the commercialization of medicines. The study was conducted with a randomized two-period crossover design (2x2) and a one-week washout period, the same volunteers received, in each period, a test formulation or a reference formulation. The treatment sequence was determined by a randomization list, automatically produced by Medicines Clinical Trials Control System. Plasma samples were obtained over a 36-hour interval. Cefadroxil concentrations were analyzed by combined high pressure liquid chromatography and UV-visible detection (HPLC-UV). From the Cefadroxil plasma concentration vs time curves the following pharmacokinetic parameters were obtained: 'AUC IND. 0-t ', 'AUC IND. 0-INFINITO¿ and 'C IND. max¿. The Geometric mean of Cefadroxil / Cefamox 500 mg for individual percentage ratio was 105.58% (90% CI=102.17%; 109.10%) for an area under the cefadroxil plasma concentration versus time curves (0-t), 104.74% (90% CI= 101.55%; 108.02%), for an area under the cefadroxil plasma concentration versus time curves ('0-INFINITO¿), and 112.08% (90% CI=105.59%; 118.97%) for maximum observed plasma concentration. Conclusion: Since 90% CI for both 'C IND. max¿, 'AUC IND. 0-t ', and 'AUC IND. 0-INFINITO¿ were within the 80-125% interval proposed by the RDC 135 (ANVISA/may 2003), it was conc1uded that Cefadroxil - capsule 500 mg was bioequivalent to Cefamox, according to both the rate and the extension of absorption / Mestrado / Mestre em Farmacologia

A avaliação biofarmacêutica de formas farmacêuticas contendo ampicilina foi realizada em dois lotes de cápsulas e dois de suspensão oral. O estudo da bioequivalência seguiu delineamento experimental cruzado, com dois períodos, empregando 16 voluntários de ambos os sexos (7 homens e 9 mulheres), com idades entre 21 e 26 anos (média de 23 anos) e peso entre 48 e 105 Kg (média de 68,2 Kg), dentro do intervalo de 10 % do peso ideal. Exames clínicos e laboratoriais foram realizados para selecionar os voluntários, sendo excluídos aqueles que apresentaram alguma alteração nos parâmetros clínicos normais ou com histório de reação alérgica às penicilinas e, ainda, os indivíduos que estivessem fazendo uso de medicamentos a menos de uma semana da realização do estudo. O protocolo experimental foi aprovado previamente pela Comissão de Ética do Hospital Universitário (HUUSP). Os ensaios de bioequivalência foram efetuados em períodos distintos para cada forma farmacêutica, com uma semana de intervalo. No dia dos testes e após jejum de 12 horas, os voluntários foram divididos em dois grupos com igual número de indivíduos, sendo que, a cada grupo foi administrada dose única de 500 mg de ampicilina de lotes diferentes. Após período de wash out de 48 horas, a administração dos produtos aos grupos foi invertida para que todos os indivíduos recebessem ambos os produtos. A determinação quantitativa da ampicilina foi realizada em amostras de urina coletadas num período de doze horas, aplicando o método espectrofotométrico, com leituras a 320 nrn, após reação a 70° C em solução tampão fosfato/sulfato de cobre por 30 minutos. Os parâmetros farmacocinéticos calculados foram: quantidade acumulada de ampicilina na urina (Xuacumul), velocidade máxima de excreção urinária (Vmáx), tempo no qual essa velocidade foi atingida (tmáx), constantes de velocidade de eliminação (K) e de excreção urinária (ku)e a meia-vida de eliminação (t1/2). A recuperação de ampicilina inalterada na urina variou de 54,5 a 58,9 % e de 54,6 a 57,8 % das doses administradas para cápsulas e suspensão, respectivamente; a meia-vida média calculada foi de 1,9 h para cápsulas e de 1,7 h para suspensão. Os intervalos de confiança (α= 0,10) calculados para a razão das médias das quantidades acumuladas de ampicilina estão contidos no limite de 80 a120 %. A análise estatística dos resultados aplicando métodos paramétrico (ANOVA) e não paramétrico (Mann-Whitney), conforme as normas preconizadas pelo FDA, comprovou que não há diferenças significativas (nível de significância de 90 %) entre os produtos A e B quanto aos parâmetros estudados. / A biopharmaceutic quality evaluation of two brands of ampicillin capsule and suspension dosage forms is presented. The bioequivalence study was based on an open randomized two-period crossover design with 7 male and 9 female healthy volunteers, aged 21 to 26 years (mean 23 yr) with body weights ranging from 48 to 105 Kg (mean 68,2 Kg) and within 10 % of the ideal body weight. All subjects passed by routine clinical and laboratory examinations. The volunteers had no histories of alergic reaction to penicillins and no other drugs were taken for at least 1 week before starting the study. The clinical protocol was approved by the Ethics Committee ofthe University Hospital (HUUSP). Studies were conducted separately for each dosage form after 1 week interval. On the day of the study, following an overnight fast, subjects were divided into two groups, each receiving 500 mg single dose of one of the two ampicillin dosage form. After a 2-day washout period, the same products were given in inversed order. Ampicillin data were obtained from urine samples collected over a 12 hour period. A spectrophotometric measurement at 320 nm after reaction in copper-phosphate/sulfate buffer solution at 70°C for 30 minutes was used. Total cummulative urinary excretion (Xuacumul), urinary excretion rates (Vmax), time to peak (tmax), urinary excretion rate constants (ku), elimination rate constants (K), and elimination half lives (t1/22) were calculated. Mean urine unchanged ampicillin recoveries of administered doses ranged from 54,5 to 58,9 % for capsules and from 54,6 to 57,8% for suspensions; t1/2 ranged from 1,7 to 1,9 h. Confidence intervals (α=0,10) for average rates were within 80-120 %. Statistic parametric (ANOVA) analysis and non-parametric analysis (Mann-Whitney) showed non-significance differences on the studied parameters of the two products at 90% significance leveI, according to FDA regulations.

In recent years, the development of follow-on biological products (biosimilars) has received increasing attention. The dissertation covers statistical methods related to three topics of Non-inferiority (NI), Bioequivalence (BE) and Equivalence in demonstrating biosimilarity. For NI, one of the key requirements is constancy assumption, that is, the effect of reference treatment is the same in current NI trials as in historical superiority trials. However if a covariate interacts with the treatment arms, then changes in distribution of this covariate will result in violation of constancy assumption. We propose a modified covariate-adjustment fixed margin method, and recommend it based on its performance characteristics in comparison with other methods. Topic two is related to BE inference for log-normal distributed data. Two drugs are bioequivalent if the difference of a pharmacokinetics (PK) parameter of two products falls within prespecified margins. In the presence of unspecified variances, existing methods like two one-sided tests and Bayesian analysis in BE setting limit our knowledge on the extent that inference of BE is affected by the variability of the PK parameter. We propose a likelihood approach that retains the unspecified variances in the model and partitions the entire likelihood function into two components: F-statistic function for variances and t-statistic function for difference of PK parameter. The advantage of the proposed method over existing methods is it helps identify range of variances where BE is more likely to be achieved. In the third topic, we extend the proposed likelihood method for Equivalence inference, where data is often normal distributed. In this part, we demonstrate an additional advantage of the proposed method over current analysis methods such as likelihood ratio test and Bayesian analysis in Equivalence setting. The proposed likelihood method produces results that are same or comparable to current analysis methods in general case when model parameters are independent. However it yields better results in special cases when model parameters are dependent, for example the ratio of variances is directly proportional to the ratio of means. Our research results suggest the proposed likelihood method serves a better alternative than the current analysis methods to address BE/Equivalence inference.

A highly sensitive and rapid method for the analysis of isradipine in human plasma using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed. The procedure involves a simple liquid-liquid extraction of isradipine and amlodipine (IS, internal standard) with methyl-t-butyl ether after alkaline treatment and separation by RP-HPLC. Detection was performed by positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode, monitoring the transitions m/z 372.1 → m/z 312.2 and m/z 408.8 → m/z 237.9, for quantification of isradipine and IS, respectively. The standard calibration curves showed good linearity within the range of 10 to 5000 pg/mL (r2 ≥ 0.9998). The lower limit of quantitation (LLOQ) was 10 pg/mL. The retention times of isradipine (0.81 min) and IS (0.65 min) suggested the potential for high throughput of the proposed method. In addition, no significant metabolic compounds were found to interfere with the analysis. This method offered good precision and accuracy and was successfully applied for the pharmacokinetic and bioequivalence studies of 5 mg of sustained-release isradipine in 24 healthy Korean volunteers.

Background: Aceclofenac is a phenylacetic acid derivative with analgesic and anti-inflammatory properties and an improved gastrointestinal tolerance compared with other NSAIDs, such as diclofenac. Objective: This study was conducted to compare the bioavailability of 2 branded formulations of aceclofenac 100 mg (test and reference) marketed in Korea. Methods: This single-dose, randomized, open-label, 2-period crossover study in healthy Korean adult volunteers was conducted at Hanyang University Medical Center (Seoul, Republic of Korea). Subjects received 1 tablet of each aceclofenac 100-mg formulation. Study drugs were administered with 240 mL of water after a 10-hour overnight fast on each of 2 treatment days separated by a 1-week washout period. After study drug administration, serial blood samples were collected over a period of 12 hours. Plasma was analyzed for aceclofenac concentration using a validated high-performance liquid chromatography method with visible detection in the range of 0.1 to 20 μg/mL, with a lower limit of quantitation of 0.1 μg/mL. Several pharmacokinetic (PK) parameters, including Cmax, Tmax, t1/2, AUC0-t, AUC0-∞, and ke, were determined from the plasma concentrations of the 2 aceclofenac formulations. Cmax, AUC0-t, and AUC0-∞ were used to test for bioequivalence after log-transformation of plasma data. The predetermined, regulatory range of 90% CI for bioequivalence was 0.80 to 1.25. Results: A total of 24 subjects were enrolled (20 men, 4 women; mean [SD] age, 23.5 [1.4] years; mean [SD] weight, 68.1 [11.5] kg). No significant differences were found based on analysis of variance, with mean values and 90% CIs of test/reference ratios for these parameters as follows: Cmax, 10.57 versus 9.79 μg/mL (0.961-1.225); AUC0-t, 19.95 versus 19.93 μg · h/mL (0.937-1.037); and AUC0-∞, 20.75 versus 20.48 μg · h/mL (0.949-1.049). Conclusion: In these healthy Korean volunteers, results from the PK analysis suggested that the test and reference formulations of aceclofenac 100-mg tablets were bioequivalent, based on the regulatory definition.

In this dissertation a methodology is proposed for simultaneously evaluating the population bioequivalence (PBE) of a generic drug to a pre-licensed drug, or the bioequivalence of two formulations of a drug using multiple correlated pharmacokinetic metrics. The univariate criterion that is accepted by the food and drug administration (FDA) for testing population bioequivalence is generalized. Very few approaches for testing multivariate extensions of PBE have appeared in the literature. One method uses the trace of the covariance matrix as a measure of total variability, and another uses a pooled variance instead of the reference variance. The former ignores the correlation between the measurements while the later is not equivalent to the criterion proposed by the FDA in the univariate case, unless the variances of the test and reference are identical, which reduces the PBE to the average bioequivalence. The confidence interval approach is used to test the multivariate population bioequivalence by using a parametric bootstrap method to evaluate the 100% (1-alpha) confidence interval. The performance of the multivariate criterion is evaluated by a simulation study. The size and power of testing for bioequivalence using this multivariate criterion are evaluated in a simulation study by altering the mean differences, the variances, correlations between pharmacokinetic variables and sample size. A comparison between the two published approaches and the proposed criterion is demonstrated. Using nonlinear models and nonlinear mixed effects models, the multivariate population bioequivalence is examined. Finally, the proposed methods are illustrated by simultaneously testing the population bioequivalence for AUC and Cmax in two datasets.

人的一生避免不了大小病痛，一但身體不適、罹患疾病，就須由醫師診斷、服用藥物；而藥物之生產首重有效與安全，要能有效的治療疾病，也要限制其毒性不超過安全限制以避免危害人體。 　　藥品之開發需要極為龐大之成本，故而各藥廠對於可以節省開發成本的藥品新劑型與學名藥之研究深感興趣；相對的，也就對於如何證明藥品新劑型（或學名藥）與原廠藥為生體相等可互用的方法多加探討。 　　美國FDA對於生體相等之評估準則，擬由過去的平均生體相等轉換成為個體生體相等評估準則；更改後的準則考慮面向較為完整周全，但是其應用卻須要更為繁複的試驗方式與更多的成本來配合，為了保留新準則之評估概念並簡化試驗與降低評估成本，本篇論文試圖找出新、舊評估準則之關聯，並以舊有準則為基礎做調整，盼能透過對舊準則之調整達到與新準則相類似之評估結果。如此一來，可沿用舊有試驗方法完成新準則所欲進行之評估，降低此評估研究之耗資，同時確保藥品新劑型（或學名藥）與原廠藥為生體相等可互用，具有相同療效與安全保證。

Bioequivalence determines if two drugs are alike. The three kinds of bioequivalence are Average, Population, and Individual Bioequivalence. These Bioequivalence criteria can be evaluated using aggregate and disaggregate methods. Considerable work assessing bioequivalence in a frequentist method exists, but the advantages of Bayesian methods for Bioequivalence have been recently explored. Variance parameters are essential to any of theses existing Bayesian Bioequivalence metrics. Usually, the prior distributions for model parameters use either informative priors or vague priors. The Bioequivalence inference may be sensitive to the prior distribution on the variances. Recently, there have been questions about the routine use of inverse gamma priors for variance parameters. In this paper we examine the effect that changing the prior distribution of the variance parameters has on Bayesian models for assessing Bioequivalence and the carry-over effect. We explore our method with some real data sets from the FDA.