1. Prof. Hartmut Derendorf University of Florida The Role of Pharmacological Predictors in Drug Development

2. Resistance Development

3. Approved Antibacterial Agents 1983-2004

5. Pharmacokinetics conc. vs time Conc. Time 025 0.0 0.4 PK/PD effect vs time Time Effect 0 1 0 Pharmacodynamics conc. vs effect 10 -3 Conc. (log) Effect

6. PKPD Serum MIC

7. Pharmacokinetics Problems: Protein Binding Tissue Distribution

9. vascular spaceextravascular space plasma protein binding blood cell binding, diffusion into blood cells, binding to intracellular biological material tissue cell binding, diffusion into tissue cells, binding to intracellular biological material binding to extracellular biological material

10. Azithromycin Tissue Concentrations tonsil (t)prostate (P) lung (L)serum (S) 500 mg p.o. from Foulds et al. (1990)

11. Tissue can be looked at as an aqueous dispersed system of biological material. It is the concentration in the water of the tissue that is responsible for pharmacological activity. Total tissue concentrations need to be interpreted with great care since they reflect hybrid values of total amount of drug (free + bound) in a given tissue ‘Tissue-partition-coefficients’ are not appropriate since they imply homogenous tissue distribution Tissue Concentrations

12. The free (unbound) concentration of the drug at the receptor site should be used in PK/PD correlations to make prediction for pharmacological activity

13. Blister Fluid Blister fluid is a ‘homogenous tissue fluid’ Protein binding in blister fluid needs to be considered

15. Ampicillin Cloxacillin Serum  Free blister fluid

16. Interstitium Capillary Cell Perfusate Dialysate Microdialysis

17. Cefixime (Protein binding 65%) Cefpodoxime (Protein binding 17-30%)

19. iv dose of 20 mg/kg of cefpodoxime (n=6)  plasma lung  muscle

20. Clinical study Cefpodoxime and Cefixime To compare the soft tissue distribution of these two antibiotics after 400mg oral dose in healthy male volunteers by microdialysis Two way cross-over, single oral dose study

21. Microdialysis

22. Cefixime 400 mg po Cefpodoxime 400 mg po Clinical Microdialysis Liu & Derendorf, JAC 50, 19 (2002)

23. Pharmacokinetics

24. PKPD Serum MIC

25. Ceftazidime K. pneumoniae in neutropenic mice Craig 2002

26. Temafloxacin S. pneumoniae in neutropenic mice Craig 2002

27. Pharmacodynamics Problems: MIC is imprecise MIC is monodimensional MIC is used as a threshold When MIC does not explain the data, patches are used (post-antibiotic effect, sub-MIC effect)

28. MIC The Current Paradigm MIC is poison for the mind. H. Mattie (1994), after a long after-dinner discussion

29. Auto-dilution system flask reservoir tubing connector pump waste Kill Curves

30. H. influenzae ATCC10211 MIC: 5 ng/mL S. pneumoniae ATCC6303 MIC: 20 ng/mL Kill Curves of Ceftriaxone

31. S. pneumoniae ATCC6303 MIC: 20 ng/mL H. influenzae ATCC10211 MIC: 5 ng/mL Kill Curves of Ceftriaxone

32. Maximum Growth Rate Constantk Maximum Killing Rate Constantk-k max PK-PD Model Initially, bacteria are in log growth phase

33. Single Dose Piperacillin vs. E. coli

34. Dosing Interval Piperacillin (2g and 4g) vs. E. coli q24h q8hq4h

35. PK-PD Model In animals Bacterial survival fraction of P. aeruginosa in a neutropenic mouse model at different doses (mg/kg) of piperacillin (Zhi et al., 1988)

36. FDA Draft-Guidance for Industry (1997) Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products New Dosage Form of a Previously Studied Drug In some cases, modified release dosage forms may be approved on the basis of pharmacokinetic data linking the new dosage form from a previously studied immediate-release dosage form. Because the pharmacokinetic patterns of controlled-release and immediate release dosage forms are not identical, it is generally important to have some understanding of the relationship of blood concentration to response to extrapolate to the new dosage form.

37. Plasma and free tissue levels n = 12 (means +/- S.D.) total plasma concentrations  free tissue concentrations 500 mg IR

38. Plasma and free tissue levels n = 12 (means +/- S.D.) total plasma concentrations  free tissue concentrations 500 mg MR750 mg MR

39. Cefaclor 750 mg MR bid vs 500 mg IR tid

40. Resistance Modeling Pre-existing subpopulations Emerging subpopulations Adaptive resistance (transporters)

41. Drug (C) f s (C) Growth ( k 0 ) f r (C) Bacteria (R) Bacteria (S) Bacteria pool Killing Two sub-population model OBS: same growth rate for sensitive (S) and resistant (R)

42. Two sub-population E max model

43. Dose ka Cp ke  kill (-) Cr k 0 k ecr Bacteria Comparing to E max model: Modified E max Model:

44. Two sub-population model (simultaneous fit) Modified E max model (simultaneous fit) Model Comparison – E. coli

45. A simple comparison of serum concentration and MIC is usually not sufficient to evaluate the PK/PD- relationships af anti-infective agents. Protein binding and tissue distribution are important pharmacokinetic parameters that need to be considered. Microdialysis can provide information on local exposure. PK-PD analysis based on MIC alone can be misleading. Microbiological kill curves provide more detailed information about the PK/PD-relationships than simple MIC values. Summary

46. Proposal Wild Card Patent Extension A company that receives approval for a new antibiotic, or a new indication for an existing antibiotic, that treats a targeted pathogen would be permitted to extend the market exclusivity period for another of the company’s FDA-approved drugs.

47. ISAP International Society of Anti- Infective Pharmacology Workshops at ECCMID and ICAAC Symposia at ECCMID and ICAAC Joint Symposium with FDAand IDSA Website with slides, presentations and tons of information www.isap.org

48. Acknowledgements Edgar Schuck Qi Liu Ping Liu Teresa Dalla Costa Amparo de la Peña Ariya Khunvichai Arno Nolting Wanchai Treeyaprasert Stephan Schmidt Elizabeth Potocka Martin Brunner Markus Müller Kenneth Rand Alistair Webb Maria Grant Andreas Kovar Olaf Burkhardt Vipul Kumar Yanjun Li Oliver Ghobrial April Barbour