PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com Abstract is available at http://www.pharmaconnectme.com

3. Patent EQUIVALENCE BETWEEN CLINICAL TRIAL AND MARKET FORMULATIONS

4. APPROVAL PATENT EXCLUSIVITY EXPIRATION M.A. APPLICATION INNOVATOR MANUFACTURER EF FICACY SAFETY SPECIFICATIONS FORMULATION QUALITY AND PERFORMANCE ESSENTIAL SIMILARITY TIME SECOND APPLICANTS VARIATIONS ESSENTIAL SIMILARITY ESSENTIAL SIMILARITY

5. CATENARY CHAIN TYPE OF MODEL FOR IV/IV and PK/PD Effect Compt Dose IV/IV Correlation PK/PD Relationship Metabolite(s) Tissue binding Solution Plasma concentration Urine Surrogate end-points Main clinical end-point PK surrogate

7. Dissolution, Intestinal absorption and pre-systemic elimination processes for an orally administered solid dosage form Dose Metabolic site (gut wall, liver ) Solution dissolution Pre-systemic elimination Absolute or Pharmacological Bioavailability Relative or Pharmaceutical Bioavailability absorption permeation Plasma concentration

8. ABSOLUTE, RELATIVE BIOAVAILABILITY ACCORDING TO SITES OR PROCESSES OF LOSS BIOAVAILABLE DOSE: F.F*.D DOSAGE FORM delivery DRUG IN G.I. FLUIDS dissolution DRUG IN SOLUTION AT THE uptake SITES removal G.I . TRACT GUT WALL PORTAL VEIN LIVER GENERAL CIRCULATION SITE OF MEASUREMENT 1-F G 1-F H 1-F F* = F G .F H

10. FITTED CURVES TO MEAN ALLOPURINOL AND OXYPURINOL PLASMA CONCENTRATIONS: TREATMENTS U AND Z Allopurinol Oxypurinol Time (h) Plasma Conc. (mg/ L) t max C max AUC

12. RELATIONSHIP BETWEEN DIFFERENT DEFINITIONS ESSENTIAL SIMILARITY SAME DOSE FORM SUBSTANCE BIOEQUIVALENCE BIOAVAILABILITY SAME ACTIVE MOIETY THERAPEUTIC EQUIVALENCE PHARM. EQUIVALENCE SAME DOSE FORM SUBSTANCE (different excipients & manufacture) PHARM. ALTERNATIVE DIFFERENT DOSE FORM CHEMISTRY

15. Extension of the essential similarity definition The extension of the essential similarity definition to other chemical forms, including isomers, and to all oral immediate release pharmaceutical forms entails a sizeable risk, even if bioequivalence is demonstrated according to the relevant guidelines and the safety of the counter ion in the case of salts is ensured.

16. Extension of the essential similarity definition There are too many uncontrolled events in the way the body handles these substances that cannot be pinned down by just a human pharmacokinetic or a safety animal study. In the absence of hard scientific evidence this definition entails unknown risks.

17. RELATIONSHIP BETWEEN DIFFERENT DEFINITIONS ESSENTIAL SIMILARITY SAME DOSE FORM SUBSTANCE BIOEQUIVALENCE BIOAVAILABILITY PHARM. EQUIVALENCE SAME DOSE FORM SUBSTANCE (different excipients & manufacture) PHARM. ALTERNATIVE DIFFERENT DOSE FORM CHEMISTRY SAME ACTIVE MOIETY NEW DEFINITION OF GENERIC MED. PRODUCT

18. Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98 – 26 July de 2001 Immediate Release Medicinal Products

31. Lansoprazole Case Study Point estimate (90% CI) 0.82 (0.70-0.97) 0.97 (0.80-1.17) C max 1.03 (0.92-1.15) 1.02 (0.89-1.18) AUC inf 0.95 (0.86-1.04) 1.03 (0.89-1.18) AUC 0-t Fed (low-fat) Fasted

32. Health concerns Only BE under fasted conditions. Not BE under low-fat fed conditions Moreover, effect of high-fat may well be greater Conclusion Dose-dumping can not be excluded => additional BE study under high-fat conditions needed. Lansoprazole Case Study

37. Bioavailability/Bioequivalence Study Último tempo de amostragem AUC 0-t AUC t-  t max C max 16,91 14,0 5,68 20,97 26,19 31,94 36,81 47,96 64,39 91,21 104,28 114,80 119,27 127,98 116,86 78,47 0,00 Conc. Tramadol (ng/mL) 24,0 13,0 12,0 11,0 10,0 8,00 6,00 4,00 3,00 2,50 2,00 1,50 1,00 0,66 0,00 Tempo (horas)

38. Ln C= Ln C e - k e t Cálculo do k e regressão linear com os pontos terminais do gráfico Ln concentração vs tempo t 1/2 =(ln2)/k e = 4,79h Bioavailability/Bioequivalence Study 16,91 14,0 5,68 20,97 26,19 31,94 36,81 47,96 64,39 91,21 104,28 114,80 119,27 127,98 116,86 78,47 0,00 Conc. Tramadol (ng/mL) 24,0 13,0 12,0 11,0 10,0 8,00 6,00 4,00 3,00 2,50 2,00 1,50 1,00 0,66 0,00 Tempo (horas)

39. Bioavailability/Bioequivalence Study Extent of absorption: AUC C max time Plasma Concentration t max C max AUC Rate of absorption: C max t max AUC dif. C max same time Plasma Concentration t max C max AUC AUC same C max dif. C max t max

43. Metabolite Case Study Conclusion: BE is declared on the basis of the analyte that is quantified with most reliability, but the other species has to comply with wider acceptance limits. According to a more strict view, if bioequivalence cannot be established for the parent compound, then the test is not bioequivalent to the reference 83,0 – 109 76.3 – 98.2 C max 96.2 – 118 77,1 – 99,0 AUC 0-  96,1 – 124 76.1 – 99.5 AUC 0-t (  -hidroxi-simvastatine) Simvastatine 90% CI (%) for GMR Test/Reference

46. ANOVA TABLE Source of variation df SS MS=SS/df F P Subjects 11 1.5845 Sequences 1 0.0012 0.0012 0.008 0.93 Subject within sequence 10 1.5833 Periods 1 0.2441 0.2441 8.360 0.02 Formulations 1 0.0305 0.0305 1.045 0.33 Residual 10 0.2915 s 2 =0.0292 Total 23 2.1510

47. Statistical analysis example -hydrochlorothiazide [84,5 – 106]% 94,7% AUC 0-inf [87,6 – 106]% 96,8% AUC 0-t [85,3 – 101]% 93,0% C max 90% CI  T /  R Parameter

49. Performance of CI approach 75 80 100 125 133 1 1 2 2 3 4

50. Performance of CI approach Nightingale and Morrison, JAMA 258: 1200-1204, 1987

51. Performance of CI approach J.E. Henney, JAMA 282: 1995, 1999 For 127 in vivo bioequivalence studies

64. Highly Variable Example Exemplo: Teste vs. Referência em 36 voluntários para um fármaco com elevada variabilidade (C.V. >60%) 1.21 1.33 Limite superior 0.87 0.83 Limite inferior Intervalo Confiança a 90% 1.01 1.05 Razão das médias geom.(Teste/Referência) 79 ± 48 212 ± 129 Referência 80 ± 62 224 ± 146 Teste C max AUC Estudo de Biodisponibilidade / Bioequivalência

65. M. Tanguay et al., AAPS Abstract, Novembro 2002 (Dados obtidos a partir de 800 estudos em jejum) Bioavailability/Bioequivalence Study 62% >30% 26% 20-30% 10% 10-20% 6% < 10% Non Bioequivalent studies(%) Intra-individual CV%

67. Probability that 90% CI falls within 80 – 125% in a 2-way cross-over for CV=15% and 30% with 20 subjects 100% 45% CV=15% CV=30% N=88 subjects

71. Pharmacokinetics of Omeprazole after single and multiple oral dose: Clear proof of non-linearity after repeated doses: Omeprazole CMD referral (Andersson T et al: Drug Invest 1991) 4.92 2.14 1.51 0.79 0.46 0.24 Repeated oral doses 1.79 0.98 0.89 0.52 0.38 0.25 Single oral dose AUC (µmol/lxh) Cmax (µmol/l) AUC (µmol/lxh) Cmax (µmol/l) AUC (µmol/lxh) Cmax (µmol/l) 40 mg 20 mg 10 mg 2.82 1.69 1.21 2.66 1.63 1.15 1.17 AUC Ratios 40 mg 20 mg 10 mg 40 mg : 10 mg 20 mg : 10 mg 40 mg : 10 mg 20 mg : 10 mg Day 5 : Day 1 Day 5 Day 1

72. Reduced degradation of omeprazole by gastric acid – the evidence: Omeprazole CMD referral Increase of AUC after 5 days with i.v. administration Increase of AUC after 5 days with oral administration (Andersson T et al: 1991) (Cederberg C et al: 1992) 2.82 1.69 1.21 AUC Ratios 40 mg 20 mg 10 mg Dose Day 5 : Day 1 Oral 1.88 1.88 1.18 AUC Ratios 1.88 8.14 1.17 AUC - day 5 1.00 4.32 0.99 AUC - day 1 20 mg oral 40 mg i.v. 10 mg i.v. µmolxh/l

73. Omeprazole CMD referral Conclusions: ▪ There is a significant increase of C max and AUC in omeprazole kinetics over time which is not only caused by inhibition of drug metabolising enzymes but also by reduced acid degradation. ▪ Therefore, the acid resistant properties of a formulation need to be tested not only in single-dose studies, but also in multiple-dose studies mimicking the pH environment of a prolonged administration of the drug

75. Steady-state extrapolation example Single dose data modelled as a 2 compt model with 1st order input and a lag time

76. Steady-state extrapolation example Steady state extrapolation using 2 compt model with terminal t 1/2 = 12 h Steady state extrapolation using 2 compt model with terminal t 1/2 = 144 h for T and 111 h for R It is concluded that the single-dose AUC 0-∞ underestimates the amount absorbed in both formulations and, in future studies, a longer measurement should be made.

77. Steady-state extrapolation with food effect The above simulation allows quantifying the magnitude of the underestimation of the food-induced increase in Cmax

78. Steady-state extrapolation with food effect Simulated placebo corrected profiles for systolic blood pressure responses to 1. single dose under fed & fasted conditions 2. steady state after high fat meal

84. Figure 1: Plot of AUC vs. dose for a drug that exhibit non-linear pharmacokinetic characteristics resulting in greater than proportional increases in AUC with increases in dose. Figure 2: Plot of AUC vs. dose for a drug that exhibit non-linear pharmacokinetic characteristics resulting in less than proportional increases in AUC with increases in dose. Dose proportionality

85. Muito obrigado