Dúvidas denucci@ gdenucci .com Arquivo Protocol development ­ Evaluation and Decision.ppt Site www.gdenucci.com

1. Dúvidas denucci@gdenucci.com Arquivo Protocol development ­ Evaluation and Decision.ppt Site www.gdenucci.com

3. Bioavailability The fraction of unchanged drug reaching the systemic circulation by whatever route of administration • Absolute bioavailability – oral route compared to IV route • Relative bioavalability – oral route compared to a standard oral dosage form

4. BIOAVAILABILITY CAN BE DETERMINED BY MEASUREMENTS OF • Concentration of the active drug or metabolite(s) in biological fluid as a function of time. • Urinary excretion of the active drug or metabolite(s) as a function of time. • Any appropriate acute pharmacological effect.

5. Equivalence • Comparative bioavailability (bioequivalence) studies in humans • Comparative pharmacodynamic studies in humans • Comparative clinical trials • In vitro dissolution tests (in certain circumstances – approximately 25%)

6. D [%] [ng/ml] [min] [h] SocraTec R & D

7. D [%] [ng/ml] [min] [h]

8. Fundamental Bioequivalence Assumption When two drug products are equivalent in the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed and becomes available at the site of drug action, it is assumed that they will be therapeutically equivalent.

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

10. Pharmacokinetic parameters 8 6 4 2 0 Cmax Concentration tmax 0 3 6 9 12 Hours

11. Pharmacokinetic parameters 8 6 4 2 0 Concentration AUC 0-12h 0 3 6 9 12 Hours

12. Design and analysis of average bioequivalence studies

13. Design Sequence Period 1 Period 2 • 2x2 cross-over • washout to avoid carry-over effects • also in food-interaction • drug-drug-interaction studies may consider “one-sequence cross-over” or parallel group designs 1 Reference Test 2 Test Reference

14. Bioequivalence study using two parallel groups • study can be completed quickly, no washout necessary • analysis based on inter-subject variability, which is generally much higher than intra-subject variability: much more subjects needed

15. Situations in which a parallel design may be appropriate • long half-life ( long washout necessary in a crossover study) • subjects are very ill patients • high drop-out rate per period • cost of increasing the number of subjects is much less than that of adding an additional period

16. Criteria Mean(AUCtest) / Mean (AUCreference)  (80%, 125%) Mean(Cmaxtest) / Mean (Cmaxreference)  (80%, 125%)

17. SocraTec R & D

18. SocraTec R & D

19. SocraTec R & D

22. Problemas de Bioequivalência 1 - Produto de referência 2 - Critérios para aferição da bioequivalência (intervalos muito grandes ou muito curtos dependendo do produto) 3 - Validade do teste de bioequivalência 4 - Desenho dos estudos (dose única, dose múltipla, etc).

23. Concentration Mean

24. Statistical Analysis for BE 90% CI Parameters OH-Clarithromycin Clarithromycin 91.1 - 103.7 94.2 - 108.1 AUC % ratio (0 - last) AUC % ratio 93.9 - 107.2 91.0 - 103.4 (0 - inf) 92.3 - 116.8 C % ratio 87.5 - 108.7 max

25. Concentration Mean Diazepam Valium 300 Test formulation 200 (ng/mL) Concentration 100 0 0 4 8 12 16 20 24 48 96 144 192 240 Time (h)

26. 40 30 20 10 0 0 4 8 12 16 20 24 Concentration MeanNordiazepam Valium Test formulation (ng/mL) Concentration 48 96 144 192 240 Time (h)

27. Statistical Analysis for BE 90% CI Parameters Nordiazepam Diazepam 89.00 - 106.65 88.70 - 108.91 AUC % ratio (0 - last) AUC % ratio 102.55 - 169.37 88.81 - 108.43 (0 - inf) 88.28 - 107.52 C % ratio 50.27 - 72.42 max

28. Statistical Analysis for BE 90% CI Parameters Risperidone OH-Risperidone AUC % ratio 94.26 % - 105.94 % 78.60 % - 98.28 % (0 - last) AUC % ratio 79.30 % - 98.95 % 92.54 % - 105.08 % (0 - inf) C % ratio 86.37 % - 99.09 % 71.55 % - 92.91 % max

29. How do get them? • Commercialy available • Chemical synthesis • Biological synthesis • Recovery from biological samples

30. Chemical synthesis • Expensive • Technically difficult

31. Biological synthesis • Enzymes (bacteria, microsomes, hepatocytes, etc). • Requires very good efficacy

32. Recovery from biological samples • Previous administration to volunteer (recovery from urine)

33. Not available Measurable (expressed as equivalents of parent)

34. Statistical Analysis for BE 90% CI Parameters Fluoxetine Norfluoxetine AUC % ratio 99.4 - 115.7 101.6 - 121.0 (0 - last) AUC % ratio 101.3 - 120.5 99.4 - 115.6 (0 - inf) C % ratio 85.2 - 102.2 86.1 - 102.6 max

36. Bioavailability study comparing one test formulation of Paracetamol / Dimethinden Maleate / Phenylephrine hydrochloride (Trimedal - tablet for 500 / 1.0 / 10 mg, respectively; NOVARTIS Biociências S.A.) versus reference tablet products (Paracetamol 500 mg, Dimethinden Maleate 1.0 mg, Phenylephrine hydrochloride 10 mg individually administered; NOVARTIS Biociências S.A.) in healthy volunteers of both genders

37. OBJECTIVE • The present study was conducted to evaluate the pharmacokinetic profiles of the combination formulation – Trimedal [Paracetamol / Dimethindene / Phenylephrine] (formulation 1 – test product) against the individual administration of each of its compounds in order to evaluate the influence of the coadministration.

38. PLASMA CONCENTRATIONS VS. SCHEDULED BLOOD SAMPLING TIME USING IN LINEAR SCALE (PHENYLEPHRINE)

39. PLASMA CONCENTRATIONS VS. SCHEDULED BLOOD SAMPLING TIME USING IN LINEAR SCALE (DIMETHINDENE)

40. PLASMA CONCENTRATIONS VS. SCHEDULED BLOOD SAMPLING TIME USING IN LINEAR SCALE (PARACETAMOL)

41. DIMETHINDENE PHARMACOKINETIC PARAMETERS

42. PHENYLEPHRINE PHARMACOKINETIC PARAMETERS

43. PARACETAMOL PHARMACOKINETIC PARAMETERS

44. PARAMETRIC POINT ESTIMATES AND 90% CONFIDENCE INTERVALS DETERMINED FOR CMAX AND AUC0-TLAST

45. CONCLUSIONS • From the above results it can be concluded: • DIMETHINDENE: the addition of Paracetamol and Phenylephrine in the Test Product does not interfere with the action of Dimethindene, since the Cmax and AUC(0-last) pharmacokinetic parameters are within the expected values reported in the literature. • PHENYLEPHRINE:The results for Phenylephrine conform to the reported literature as a highly variable drug (power of 0.39 for AUC in contrast with the power ~1.00 obtained for the other formulation compounds). From the results it can be concluded that the addition of Paracetamol and Dimethindene in the combination formulation - Trimedal (formulation 1 -test product) does not inhibit Phenylephrine absorption. Therefore it should not impair Phenylephrine therapeutic effect. • PARACETAMOL: it can be concluded that the addition of Dimethindene and Phenylephrine in the Test Product does not interfere with the action of Paracetamol, since the Cmax and AUC(0-last) pharmacokinetic parameters are within the expected values reported in the literature.

46. Bioavailability Study comparing one Spironolactone formulation from Laboratórios Biosintética Ltda (tablet 100 mg) with a marketed reference product Aldactone (tablet 100 mg) in healthy volunteers

47. OBJECTIVE • The objective of this study was to the assessment of relative bioavailability of 2 products in order to determine whether they are bioequivalent. • Test: Aldactone - 100 mg tablet - single dose, oral administration; • Reference: Aldactone 100 mg tablet- single dose, oral administration;

48. PLASMA CONCENTRATIONS VS. SCHEDULED BLOOD SAMPLING TIME USING IN LINEAR SCALE (SPIRONOLACTONE)

49. PLASMA CONCENTRATIONS VS. SCHEDULED BLOOD SAMPLING TIME USING IN LINEAR SCALE (CANRENONE)

50. SPIRONOLACTONE PHARMACOKINETIC PARAMETERS