A Research Report submitted to the Faculty of Science in partial fulfilment of the requirements for the degree of Master of Science. 26 October 2016. / The cost of healthcare has become generally expensive the world over, of which the greater part of the money is spent buying drugs. In order to reduce the cost of drugs, drug manufacturers came up with the idea of manufacturing generic drugs, which cost less as compared to brand name drugs. The challenge which arose was how safe, effective and efficient the generic drugs are compared to the brand name drugs, if people were to buy them. As a consequence of this challenge, bioequivalence studies evolved, being statistical procedures for comparing whether the generic and brand name drugs are similar in treating patients for various diseases. This study was undertaken to show the existence of bioequivalence in drugs. Bioavailability is considered in generic drugs to ensure that it is more or less the same as that of the original drugs by using statistical tests. The United States of America’s Food and Agricultural Department took a lead in the research on coming up with statistical methods for certifying generic drugs as bioequivalent to brand name drugs. Pharmacokinetic parameters are obtained from blood samples after dosing study subjects with generic and brand name drugs. The design for analysis in this research report will be a 2 2 crossover design. Average, population and individual bioequivalence is checked from pharmacokinetic parameters to ascertain as to whether drugs are bioequivalent or not. Statistical procedures used include confidence intervals, interval hypothesis tests using parametric as well as nonparametric statistical methods. On presenting results to conclude that drugs are bioequivalent or not, in addition to hypothesis tests and confidence intervals, which indicates whether there is a difference or not, effect sizes will also be reported. If ever there is a difference between generic and brand name drugs, effect sizes then quantify the magnitude of the difference. KEY WORDS: bioequivalence, bioavailability, generic (test) drugs, brand name (reference) drugs, average bioequivalence, population bioequivalence, individual bioequivalence, pharmacokinetic parameters, therapeutic window, pharmaceutical equivalence, confidence intervals, hypothesis tests, effect sizes. / TG2016

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Science in Medicine (Pharmaceutical Affairs) Johannesburg, 29 August 2014 / In South Africa’s current healthcare structure, about 8.3% of GDP is spent on healthcare. This is well above the WHO recommended 5% of GDP spend. Despite the heavy spending, health outcomes remain poor when compared to similar middle-income countries. Solutions need to be found to cut back on healthcare costs. Approximately half (4.1%) of the healthcare spend is consumed by the private sector which benefits a very small segment (16%) of the population. This segment is largely on medical schemes. Using generic medicines can aid in cutting back on drug costs but are generics being adequately assimilated by the consumers of healthcare in the private sector? The objective of the study was to evaluate the perceptions attitudes and knowledge of the consumers of healthcare in the Northern suburbs of Johannesburg towards generic medicines. A survey was conducted on a sample of 402 respondents across 9 randomly selected pharmacies in the Johannesburg north region between November 2012 and February 2013. A researcher administered questionnaire was the sole data collection tool. Questions asked covered the research objectives and also included demographic data and other explanatory variables. Data analysis was carried out in SAS. The 5% significance level was used throughout, unless specified otherwise. The chi-squared (Χ2 ) test was used to assess the relationships between categorical variables. Fisher’s exact test was used for 2 x 2 tables or where the requirements for the Χ2 test could not be met. The strength of the associations was measured by Cramer’s V and the phi coefficient respectively. Key results on respondent demographics included high representation of the higher income earning groups (78% >R10 000); furthermore 44% had completed tertiary education, 60% were comprehensively insured, 61% regularly visited a pharmacy, 38% were on prescription medication and 24% on chronic medicine. On knowledge, 5% of respondents were able to most accurately define generic medicines. On attitudes, 78% had used generics however the level of agreement was lower for the highest education category (p<0.0001; Cramer’s V=0.18). Trends favoured brands over generics with increasing severity of illness as generics were chosen by 10% in major illness and 5% in chronic illness. 80% perceived generics as safe while 95% perceived brands as safe. 75% of respondents felt that generic medicines were as effective as branded medicines. 15% indicated that branded medicines have fewer side effects. 64% showed positive perceptions of quality of generics compared to 93% for brands. Bowker’s test of symmetry was significant (p<0.0001) showing a shift towards slightly more negative perceptions towards generic medicines amongst those who thought highly of brand quality. Knowledge of generics was overall low. Perceptions regarding safety, quality, efficacy, and side effects of generic medicines were generally positive but responses proved more positive for brands. Attitudes towards generic medicines were mostly positive however willingness to use generics lessened with increasing severity of illness. Household income, health insurance (medical aid) status, level of education, experience with medicines and racial demographics played a key role in explaining consumer beliefs and behaviours. Pharmacists and Doctors had a positive influence on generic use patterns amongst other factors.

Thesis (Ph. D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Biostatistics. Title from title-page of electronic thesis. Includes bibliographical references (p. 126-131).

Abstract Background The South African Healthcare landscape has changed dramatically over the last two years with the implementation of mandatory substitution, single exit pricing and prescribed minimum benefits. The private market for medicines is becoming more competitive and commoditized. Between July 2004 and June 2005 there were 119 generic registrations at the Medicines Control Council. In the US and Canada research has been conducted on the change in prescribing behaviour induced through incentive based formularies and the impact of generic medicines on healthcare costs. This research protocol aims to build on this body of knowledge by analysing sales trends within a therapeutic class after the launch of a generic molecule in the same class. This research investigates how the introduction of generics may impact the growth of the innovator molecules and subsequent generics. The therapeutic class Acid Pump Inhibitors has been selected. Method Unit sales of Proton Pump Inhibitors are drawn monthly from sales in the total private market. They are then grouped by molecule and comparisons are drawn between the originator and it’s generic to determine association. This is also done at the aggregate level where the originators form one group and generics the second group. Each aggregate group’s average growth in the therapeutic class is then calculated to determine the aggregate group’s evolution index. Data Analysis Data is analysed through descriptive and interpretative statistics. The descriptive statistics establish a relationship between generisized molecules and the non generisized molecules. A t-test for two independent means is used to test the hypothesis that the non generisized molecules in the therapeutic class have a significant higher growth. Conclusion The results demonstrate that the number of units sold of the generisized molecules increase as they become more affordable, however contrary to intuition the number of iv units sold of the non generisized molecules also increase. The research shows that there is a statistically significant greater growth, albeit on a smaller base, of the non generisized molecules over generisized molecules.

This thesis describes a project to produce controlled release ketoprofen beads for capsules, both at Oregon State University and in an industrial scale-up operation, that are bioequivalent to the commercial product Oruvail. A bead formulation was produced by layering drug and binders in water onto nonpareil sugar seeds in a spray coating apparatus. Ketoprofen beads manufactured in this manner will immediately release their drug content in either an in vitro or an in vivo environment. Industrially produced beads were non-homogeneous in size. Large beads in a coating batch sweep up a disproportional amount of coating material leading to a thicker coating layer and decreased drug release rates. In order to predict the effects of coating modifications, an equation was developed to accurately predict the coating thickness of any material applied to spherical particles of any size. The equation developed is suggested as a replacement for one that has been in published and cited for over 20 years, but overestimates coating thickness. The bulk of this thesis details the process of altering the drug release characteristics of the beads through application of diffusional and enteric barrier coatings, and testing for bioequivalence with Oruvail through biostudy data gathered from human volunteers. Urinary drug excretion rates were measured as a substitute for timed blood sampling of the subjects. Validity of the substitution was shown. Fed state biostudies involved beads manufactured and coated at Oregon State University. Fasted state biostudies involved beads that were industrially manufactured in a scale-up operation and coated both industrially and at Oregon State University. Deconvolution, a mathematical tool, was used to determine in vivo dissolution rates and the need for further coating modification. Statistical testing using a Two 1-Sided T test was the final arbiter of whether or not bioequivalence was concluded. Bioequivalence was achieved in subjects under a fed state and finally under fasting conditions, as required by the Food and Drug Administration, with drug beads coated with ethylcellulose to slow drug release and overcoated with an enteric bather to retard early drug release. Deconvolved in vivo dissolutions originating from biostudy data were used to develop In Vitro / In Vivo Correlations (IVIVC's). IVIVC's were used to predict in vivo biostudy data from in vitro dissolution results following coating formulation modification. A practical guide for the development and use of an IVIVC was written for pharmaceutics practitioners who have an understanding of pharmacokinetics, but may lack sufficient expertise in pharmacokinetics to develop an IVIVC. / Graduation date: 1998

Thesis (M.H.A.)--University of Michigan, 1962.

Thesis (M.H.A.)--University of Michigan, 1962.

The specialised nature of the stratum corneum makes it an efficient barrier to foreign substances, including drug molecules. Therefore, cutaneous drug absorption is a slow and complex process of which stratum corneum penetration is the rate limiting step. The rate and extent of stratum corneum penetration by a drug compound depends greatly on the presence of penetration enhancing/retarding excipients and therefore the clinical outcomes of a product rely greatly on the components and quality of the formulation. Hence, establishing bioequivalence between topical products is crucial to ensure that patients receiving multisource drug products are assured of the same efficacy and safety as the brand product. Since locally acting topical formulations do not target the systemic circulation, conventional methods of assessing bioequivalence using plasma levels are not appropriate. Consequently, the current regulatory guidelines require comparative clinical trials to be carried out to show bioequivalence between topical products. As these studies are very expensive and time consuming, the development of a more direct and relatively rapid and inexpensive method for determining bioequivalence between topical products is required. Clotrimazole is an anti-fungal agent where the target site of action is in the stratum corneum. In this work, tape stripping, which involves the sampling of stratum corneum, was investigated as a tool for the determination of bioequivalence between topical clotrimazole products. The tape stripping method involved the analysis of each tape strip individually and standardization of stratum corneum thickness between subjects was carried out using TEWL measurements. This approach provided detailed information regarding the amount of clotrimazole present in the stratum corneum as well as the extent of drug penetration. Prior to the tape stripping studies an HPLC method was developed for the quantitative analysis of clotrimazole from the tape strip samples. This method was shown to be accurate and reproducible across the required range. It was also shown to be selective for clotrimazole in the presence of possible interfering substances such as those present in the tape adhesive and also skin components. The bioequivalence studies were conducted using a single “uptake” time point. In order to determine an appropriate dose duration for these studies a novel approach was employed, involving a preliminary dose duration study. For the bioequivalence investigations, Canesten® Topical cream was used as both test and reference products to determine if the method was capable of showing bioequivalence. Subsequently, Canesten® Topical cream was also compared to a 1% gel formulation to determine if the method could detect formulation differences. The conventional BE limits of 0.8 – 1.25 were used for the assessment of BE, however, the clinical relevance of using these limits for dermal studies is debatable since they are derived from oral pharmacokinetic studies. Therefore, the data from the tape stripping investigations were also assessed using more realistic limits of 0.75 – 1.33 and even 0.7 – 1.44. In addition to the tape stripping studies a novel method of determining the amount of drug present in the stratum corneum, the “Residual Method”, was investigated. This method involved assaying the amount of clotrimazole found in the residual formulation after a specified dose duration had elapsed and subtracting that amount from the amount of clotrimazole initially applied. The results of tape stripping investigations showed that, if the study is sufficiently powered, tape stripping may be used to determine bioequivalence according to the conventional limits, as well as possibly detect formulation differences between different clotrimazole products. Bioequivalence assessment using the widened intervals showed that fewer subjects were required to achieve a sufficient statistical power. The variability associated with this method was acceptable and tape stripping may therefore have the potential to be used as a BE tool in a regulatory setting for clotrimazole or other antifungal topical formulations. The “Residual Method” also showed promising results as a bioequivalence tool, but further investigation and extensive validation of this method is required before it can be suggested as a regulatory method. The results of these studies have clearly indicated that tape stripping has the potential to be used as an alternative to comparative clinical trails for the assessment of bioequivalence between clotrimazole formulations and also to assess bioequivalence between other antifungal products.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O diclofenaco sÃdico à um fÃrmaco anti-inflamatÃrio nÃo esteroidal, que exerce seus efeitos por meio da inibiÃÃo da cicloxigenase e modulaÃÃo do Ãcido araquidÃnico; apresenta propriedades analgÃsicas, sendo utilizado para tratamento sintomÃtico de dores, principalmente relacionadas à inflamaÃÃo. à um fÃrmaco de amplo uso e de fÃcil acesso para o usuÃrio. Um estudo de bioequivalÃncia refere-se à comparaÃÃo estatÃstica das principais medidas farmacocinÃticas observadas no experimento, relativas aos produtos a serem testados. Este estudo teve o objetivo de avaliar a bioequivalÃncia entre uma formulaÃÃo de diclofenaco sÃdico cÃpsulas de liberaÃÃo prolongada de 100 mg, chamada formulaÃÃo teste, versus uma formulaÃÃo de diclofenaco sÃdico cÃpsulas de liberaÃÃo prolongada de 100 mg, produto de referÃncia, em voluntÃrios sadios de ambos os sexos, em jejum e alimentados, conforme recomendaÃÃo da Anvisa. Ensaio clÃnico do tipo aberto, randomizado, cruzado, com quatro perÃodos, duas sequÃncias, nos quais os voluntÃrios receberam em cada perÃodo distinto em jejum ou alimentados, 01 cÃpsula de liberaÃÃo prolongada da formulaÃÃo teste ou 01 cÃpsula de liberaÃÃo prolongada de diclofenaco sÃdico 100 mg da formulaÃÃo de referÃncia. Em cada internaÃÃo, os voluntÃrios receberam a formulaÃÃo teste ou referÃncia acompanhada ou nÃo de uma dieta padrÃo especÃfica. As formulaÃÃes foram administradas em dose Ãnica, via oral, seguida de coletas de sangue, de pelo menos quatro meias-vidas do fÃrmaco em estudo. Os perÃodos de tratamento obedeceram a um intervalo de sete meias-vidas, entre eles (washout). As concentraÃÃes em plasma do Diclofenaco foram dosadas por mÃtodo analÃtico especÃfico e validado, baseados em cromatografia lÃquida de alta eficiÃncia acoplada à espectrometria de massa (LC-MS/MS). Os resultados mostraram que em relaÃÃo à ASCinf (Ãrea sobre a curva), os fÃrmacos nÃo foram bioequivalentes para a extensÃo da absorÃÃo. O pico de concentraÃÃo plasmÃtica (concentraÃÃo mÃxima), que indica velocidade de absorÃÃo do fÃrmaco, nÃo foi bioequivalente entre a formulaÃÃo teste e a formulaÃÃo referÃncia, estando fora do intervalo de confianÃa de 80-125%. Considerando o uso amplamente aberto do diclofenaco, ressalta-se a importÃncia em avaliar custo-eficiÃncia versus custo-efetividade quando se orienta o uso de determinada formulaÃÃo do mercado. A nÃo equivalÃncia terapÃutica pode comprometer o tratamento de um determinado sintoma, ou mesmo de uma doenÃa, podendo levar ao descrÃdito o fÃrmaco escolhido. à relevante observar que cada fÃrmaco responde a um indivÃduo de maneiras distintas, de acordo com as variaÃÃes biolÃgicas do mesmo, podendo ambas as formulaÃÃes testadas ser eficaz, mesmo nÃo sendo bioequivalentes. / Diclofenac sodium is a non-steroidal anti- inflammatory drug that exerts its effects through inhibition of cyclooxygenase and modulation of arachidonic acid; it has analgesic properties and is used for symptomatic treatment of pain, mainly related to inflammation. It is a drug widely used and easily accessible to the user. A bioequivalence study refers to the statistical comparison of the main pharmacokinetic measures observed in the experiment concerning to the products to be tested. This study aimed to evaluate the bioequivalence between a formulation of diclofenac sodium extended-release 100 mg capsules, called test formulation, versus a formulation of diclofenac sodium extended-release 100 mg capsules reference product, in healthy volunteers of both sex, fasted and fed, as recommended by ANVISA. Open-type Clinical trial, randomized , crossover, with four periods, two sequences, in which participants received in each distinct period in fasting or fed, 01 extended-release capsule of the test formulation or 01 extended release 100 mg capsule of diclofenac sodium of the reference formulation. In each hospitalization, the volunteers received the test or reference formulation with or without a specific diet pattern. The formulations were administered in a single oral dose, followed by blood sampling, at least four half-lives of study drug. Treatment periods obey an interval of seven half-lives, between then (washout). The diclofenac concentrations in plasma were dosed by a specific and validated analytical method based on liquid chromatography high efficiency coupled to mass spectrometry (LC-MS/MS). The results showed that with regard to AUCinf (area under the curve), the drugs were not bioequivalent to the extent of absorption. The peak plasma concentration (maximum concentration), which indicates the rate of absorption of the drug, was not bioequivalent between the test formulation and reference formulation, being outside the confidence interval of 80-125%. Considering the wide open use of diclofenac, it emphazises the importance of evaluate cost-efficiency versus cost-effectiveness when it guides the use of certain formulation of the market. The non therapeutic equivalence can compromise the treatment of a particular symptom, or even a disease, which may lead to discrediting the drug chosen. It is important to note that each individual responds to a drug in different ways, according to biological variations thereof, both formulations tested may be effective, although not bioequivalent.

Orientador: Gilberto de Nucci / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T11:23:53Z (GMT). No. of bitstreams: 1 Oliveira_SandroEvanirde_M.pdf: 4367932 bytes, checksum: 012ece8285397b7b316af94bf4aea91f (MD5) Previous issue date: 2006 / Resumo: O presente trabalho tem por objetivo comparar a biodisponibilidade de duas formulações de oxcarbazepina em comprimidos de 600mg, produzidas pelo Laboratório Cristália Produtos Químicos Farmacêuticos Ltda, formulação teste, com a formulação de referência Trileptal®, comprimidos 600mg, elaborada pelo Laboratório Novartis Pharma. Baseando-se na baixa variabilidade interindividual da droga e na bibliografia existente, definiu-se um número de vinte e seis voluntários de ambos os sexos, entre 18 a 50 anos, considerados sadios com base em exames físicos e laboratoriais. As amostras plasmáticas coletadas foram quantificadas por um método validado, empregando-se a cromatografia líquida de alta pressão acoplada à espectrometria de massas (LC-MS-MS). Com base nos dados da quantificação, obtiveram-se as curvas de concentração de oxcarbazepina versus tempo e seu metabólito versus tempo, determinando-se assim, os seguintes parâmetros farmacocinéticos: área sob a curva AUC ¿ área sob a curva de concentração plasmática versus tempo, concentração máxima atingida após a administração da dose (Cmax) e tempo em que ocorreu essa concentração máxima (Tmax). Concluiu-se que a formulação oxcarbazepina 600 mg produzida pelo Laboratório Cristália Produtos Químicos Farmacêuticos Ltda é bioequivalente à formulação Trileptal®, comprimido 600mg, elaborado pelo Laboratório Novartis Pharma, para extensão e taxa de absorção de oxcarbazepina, considerando-se os intervalos de confiança de 90% para as razões geométricas estabelecidos pela Food and Drug Administration (80-125%) / Abstract: The purpose of this study was to compare the bioavailability of two oxcarbazepine formulations in 600mg pills - a test formulation produced by Cristália Produtos Químicos Farmacêuticos Ltda with the Trileptal® formulation by Novartis Pharma. Based on the low interindividual variability of this drug and the existing bibliography, the study sample size indicated was 26 volunteers of both sexes, considered healthy according to their physical and laboratory exams, . The plasma samples were quantified by a validated method that used high pressure liquid chromatography with mass spectrometry (LC-MS-MS). The quantification data was used to obtain the concentration curves of oxcarbazepine versus time and metabolite versus time that determined the following pharmacokinetic parameters: the AUC curve- area under the plasma concentration versus time curve, maximum concentration achieved after the dose was administered (Cmax) and the time taken to achieve e maximum concentration (Tmax). We concluded that the 600mg oxcarbazepine formulation produced by Cristália Produtos Químicos Farmacêuticos Ltda was bioequivalent to the 600mg Trileptal® formulation produced by Novartis Pharma in relation to the rate and extent of oxcarbazepine absorption, considering confidence intervals of 90% for geometric ratios established by the Food and Drug Administration (80-125%) / Mestrado / Mestre em Clinica Medica