1. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 1 |1 | Prequalification programme: Priority essential medicines Training Workshop for evaluators from National Medicines Regulatory Authorities in the East African Community: Evaluation of quality and interchangeability of medicinal products. Dar Es Salaam United Republic of Tanzania 10 – 14 September 2007

2. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 2 |2 | Training Workshop on Evaluation of quality and interchangeability of medicinal products. Bioavailability versus bioequivalence Presenter: Drs. J. Welink Senior pharmacokineticist Medicines Evaluation Board, NL WHO adviser E-mail: j.welink@cbg-meb.nl

3. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 3 |3 | Absorption Pharmacokinetics Describe the transport processes of drugs throughout the body

4. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 4 |4 | Absorption Pharmacokinetics Use mathematical models to describe: Absorption Distribution Metabolism Excretion dA/dt = dAa/dt – k.A

5. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 5 |5 | Kinetics The Kinetic Concept receptor drug effect

6. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 6 |6 | Kinetics The Kinetic Concept receptor drug concentration effect absorption distributionelimination

7. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 7 |7 | Kinetics The Kinetic Concept absorption dissolution disintegration bioavailability

8. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 8 |8 | Bioavailability Bioavailability describes the fraction of the the dose of a drug that enters into the systemic circulation.

9. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 9 |9 | Bioavailability Bioavailability means the rate and extent to which the active substance or therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action. plasma

10. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 10 | Bioavailability Evaluation of bioavailability in vivo: extent (and rate) of absorption relative bioavailability

11. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 11 | Bioavailability oral / i.v. mass balance extent of absorption

12. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 12 | Bioavailability oral/i.v. absolute bioavailability Estimates the efficiency of absorption of the drug from the formulation versus an intravenous bolus injection F = AUC oral / AUC iv

13. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 13 | Bioavailability mass balance study radio labeled drug Recovery: - expired air - feaces - urine Urine: intact = at least abs. bioavailability Feaces: intact = may be not absorbed………

14. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 14 | Bioavailability relative bioavailability absolute bioequivalence food-effect different formulations interactions

15. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 15 | Bioavailability Relative bioavailability food effect: no change in absorption: delay in absorption: increase in absorption: decrease in absorption:

16. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 16 | Bioavailability Interactions: Absorption Distribution Metabolism Excretion food effect inhibition protein-binding displacement induction decrease increase

17. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 17 | Bioavailability Relative bioavailability diff. formulations:

18. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 18 | Bioequivalence Pharmaceutical equivalents: Medicinal products are pharmaceutical equivalents if they contain the same amount of the same active substance in the same dosage form that meet the same or comparable standard. Pharmaceutical alternatives: Medicinal products are pharmaceutical alternatives if they contain the same active moiety but differ in chemical form of that moiety or in the dosage form or strength.

19. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 19 | Bioequivalence Bioavailability Pharmaceutical equivalent Pharmaceutical alternatives

20. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 20 | Bioequivalence Bioequivalence: Two medicinal products are bioequivalent if they are pharmaceutical equivalents or alternatives and if their bioavailabilities (rate and extent) after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essential the same.

21. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 21 | Bioequivalence Essential similar products: A proprietary medicinal product will be regarded as essential similar to another product if it has the same qualitative and quantitative composition in terms of active substances, and the pharmaceutical form is the same and, where necessary, bioequivalence with the first product has been demonstrated by appropriate bioavailability studies carried out.

22. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 22 | Bioequivalence Bioequivalence: = bioavailability with pre-defined criteria for the rate and extent of absorption!!

23. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 23 | End