what do we want to avoid .

3. 1970 ~ 1980 - Bioequival�ncia e biodisponibidade da digoxina, sem a presen�a de estudos farmacocin�ticos. 1995 - E.U.A. ~ 11 milh�es de testes para monitorar drogas com I.T.E (digoxina, warfarina, etc..) 1997 - E.U.A , 3639 m�dicos - intercambi�vel - medicamento inovador por um medicamento gen�rico . Apenas 17 % dos m�dicos apresentavam o correto entendimento para identificar os padr�es t�cnicos que o FDA exige para o estudo de bioequival�ncia.

6. CONCEITO

7. Definition of Bioequivalence Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions in 3 steps : clinic,statician and analytical.

8. Parameters to establish bioequivalence Primary target variables: AUC ( or AUC(0-t) ) and Cmax Secondary target variables: tmax and t1/2

9. PHARMACOKINETIC STUDIESKEY MEASUREMENTS AUC Area under the concentration- time curve Cmax Maximum concentration A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds Tmax Time to maximum concentration Pharmacokinetic Studies. Key Measurements. To investigate the bioequivalence of 2 drug products or compounds, the FDA considers PK studies that determine the area under the concentration-time curve (AUC), maximum concentration (Cmax), and time to Cmax (Tmax) for the study compound (generic) and a reference compound (innovator).1 Each of these values for the study compound are compared with those of the reference compound. For the study and reference compounds to be considered bioequivalent, their rates and extents of absorption must not show a significant difference when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions. The red area in the diagram represents the AUC, or the extent of absorption, of the reference compound. The yellow area represents the AUC of the study compound. Cmax is an indicator of the absorption rate and Tmax is influenced by the route of compound administration. A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds. Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.Pharmacokinetic Studies. Key Measurements. To investigate the bioequivalence of 2 drug products or compounds, the FDA considers PK studies that determine the area under the concentration-time curve (AUC), maximum concentration (Cmax), and time to Cmax (Tmax) for the study compound (generic) and a reference compound (innovator).1 Each of these values for the study compound are compared with those of the reference compound. For the study and reference compounds to be considered bioequivalent, their rates and extents of absorption must not show a significant difference when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions. The red area in the diagram represents the AUC, or the extent of absorption, of the reference compound. The yellow area represents the AUC of the study compound. Cmax is an indicator of the absorption rate and Tmax is influenced by the route of compound administration. A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds. Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

10. Model of Oral Dosage Form Performance

11. Model of Oral Dosage Form Endogenous Drug Performance

12. Model of Oral Dosage Form Endogenous (KCl) Drug Performance

19. C�LCULO ESTAT�STICO An�lise param�trica e c�lculo dos intervalos: da raz�o dos medicamentos �teste� / �refer�ncia� (T/R) para valores da ASC e Cmax. Intervalo de confian�a (IC): de 90% determinado atrav�s de dois testes t unicaudais com p=0.05 (param�trico). Bioequival�ncia: IC (90%) da m�dia geom�trica (M) da ASC (extens�o da absor��o) e Cmax (velocidade de absor��o) dentro do intervalo de 80-125% da M da formula��o refer�ncia (FDA; Resolu��es 391/99 e 10/01 da ANVISA / MS).

20. AN�LISE ESTAT�STICA Softwares utilizados: WinNonLin�, Graph Pad Prism�, Excel� e Word� para Windows� Transforma��o logar�tmica: de valores da �rea Sob a Curva entre os tempos zero e �ltimo tempo, quantificado ou infinito (ASC 0-�ltimo e ASC 0-inf) e Cm�x An�lise de vari�ncia: modelo de 2 per�odos cruzados, sob os dados de ASC e Cmax transformados logaritmicamente

21. DESAFIO PRESENTE

22. EVALUATION BY ANCOVA OF COMPARATIVE BIOAVAILABILITY OF TWO ORAL FORMULATIONS OF CLOZAPINE IN STEADY STATE IN SCHIZOPHRENIC VOLUNTEERS UNDER A DIFFERENT DOSES REGIME. N. BORGES 1 MD, Ph.D, FASCPT, C. E. Sverdloff 2 M.Sc., R. Moreira2 M.D., C. Domingues2 RN, B. Borges2, 3 MS , A. Lacerda2 MD, PhD, T. Paiva2 RN, R. Moreno2 M.Sc., PhD 1 UNICAMP � State University of Campinas, Campinas, Brazil, 2 Synchrophar, Campinas, Brazil 3 College of Medicine, Pontificia Universidade Cat�lica

23. COMPARATIVE BIOAVAILABILITY STUDY OF TWO 64 �g BUDESONIDE NASAL SPRAY FORMULATIONS FOR LOCAL ACTION IN HEALTHY VOLUNTEERS.

24. IN HOUSE PROCEDURE - 1 All flasks were dully weighed in order to determine the proper function of the valves and the uniformity of the sprays.

25. IN HOUSE PROCEDURE - 2 The volunteers received the medication in a separate room, wearing protective clothes so as to avoid cross contamination. Staff members wore the same protective clothes.

26. Budesonide was quantified by HPLC MS-MS, using an API 5000. The internal standard used was 3-ceto-desogestrel.

29. BIOEQUIVAL�NCIA DE PRODUTOS ONCOL�GICOS Agradecimentos pelo convite, Represento a SynchropharAgradecimentos pelo convite, Represento a Synchrophar

30. Number of trials showing clinical equivalence of Generic and Brand- Name Drugs in cardiovascular diseaseReview and Meta-analysis ( jan-1984-aug-2008)

34. Patente expirou em Fev 07. A��es no judici�rio retardaram o lan�amento de Gen�ricos 

35. DESAFIO FUTURO

36. TEMOZOLOMIDA Descri��o geral da droga A temozolomida (TMZ) � uma prodroga que inibe a replica��o do DNA mediante metila��o das bases de nucleotidos. Tipos de tumores para os quais seu uso � mais frequente: gliomas malignos, melanomas malignos e outros c�nceres avan�ados. Resposta terap�utica similar a procarbazina e dacarbazina em glioma maligno e melanoma, respectivamente.

37. Propriedades farmacocin�ticas Em adultos e crian�as com c�ncer avan�ado, a TMZ oral (50 a 250 mg/m�) mostra PK previs�vel descritas por um modelo aberto mono-compartimental. Possui absor��o GI completa (BD=100%) e r�pida (Tmax=1 hora). O efeito da alimenta��o modifica o Tmax em 110% e atenua o Cmax e AUC.

38. Base regulat�ria FDA Tipo de estudo: jejum Design: dose �nica, cruzado, dois per�odos. Dose: 250 mg Volunt�rios: pacientes com c�ncer sob uso de TMZ ou pacientes que padeceram c�ncer e est�o em remiss�o caso os pacientes com c�ncer n�o forem suficientes.

39. Analitos a serem quantificados: TMZ em plasma. Bioequival�ncia baseada em (90%CI): TMZ Waiver de teste in vivo para doses menores Base regulat�ria FDA

40. Crit�rios inclus�o Idade: 18-70 anos Ambos os sexos Tumor s�lido com met�stase cerebral Outras op��es: gliomas malignos, melanomas malignos e outros c�nceres avan�ados, CA ov�rio recorrente, CA mama avan�ado

41. Crit�rios de exclus�o Indiv�duos com problemas de absor��o intestinal ou sujeitos a v�mito mesmo com o tratamento adequado. Indiv�duos com dificuldade de engolir medicamentos. Indiv�duos que receberam quimioterapia ou outro tratamento biol�gico antic�ncer dentro das 4 semanas antecedentes ao estudo. Indiv�duos que receberam mitomicina C ou nitrosur�ia dentro das 6 semanas antecedentes ao estudo. Radioterapia dentro das 4 semanas anteriores ao in�cio do estudo. Cirurgia dentro das 4 semanas anteriores ao in�cio do estudo. Portadores de HIV ou hepatites B ou C. Infec��o aguda que requeira tratamento com antibi�ticos.

42. Assuntos operacionais a serem definidos Locais de interna��o habilitados pela ANVISA Consulta a ANVISA acerca de interna��es em grupos de pacientes em datas diferentes. Desbalanceamento por sexo Coletas em locais e centros n�o credenciados AGRADECIMENTO REPRESENTA��O DA SYNCHROPHAR EM NOME DOS DRES MORENO E BORGESAGRADECIMENTO REPRESENTA��O DA SYNCHROPHAR EM NOME DOS DRES MORENO E BORGES

43. Capecitabina Descri��o geral: Capacetabina � um agente�citot�xico, derivado do carbamato de fluoropirimidina,�tumor-ativado e tumor-seletivo, que foi planejado para administra��o oral. Ap�s administra��o oral, a capecitabina � r�pida e extensivamente absorvida, seguida de extensa convers�o para os metab�litos, 5�-deo�xi-5-fluorocitidina (5�-DFCR) e 5�-DFUR. A administra��o com alimentos diminui a taxa de absor��o da capecitabina, por�m com m�nimo efeito sobre as �reas sob a curva (AUCs) do 5�-DFUR e de seu metab�lito subseq�ente 5-FU. Procurar guidance e paper Procurar guidance e paper

44. Capecitabina � base regulat�ria FDA Realinhar com o RafaelRealinhar com o Rafael

45. IMATINIB - GERAL O imatinib est� indicado para o tratamento de pacientes adultos com leucemia miel�ide cr�nica (LMC) � um inibidor da transdu��o do sinal celular que inibe potentemente a tirosino-quinase Bcr-Abl nos n�veis in vitro, celular e in vivo.

46. IMATINIB � BASE REGULAT�RIA FDA

52. Trap!. Is the bioequivalence study a trap ?.

53. MUITO OBRIGADO !