Monitoring tissue drug levels by microdialysis

1. Universitätsklinik für Klinische Pharmakologie Monitoring tissue drug levelsby microdialysis

2. Paul Ehrlich (1854 - 1915) “… drugs must be studied in relation to their affinity for particular targets …” Corpora non agunt nisi in loco apto The Nobel Museum

3. Conventional Assumption (1) “Blood / Target equilibrium can be taken for granted” Drug distribution can solely be explained by laws of diffusion

4. Active TransportersSchinkel et al. J Clin Invest 1995

5. Distribution is not always driven by instantaneous diffusion Equilibrium at steady state (but delayed) • capillary density and blood flow (Krogh cylinder) • capillary permeability Inequilibrium at steady state • active transporters (e.g. P-GP) • pH - partition • Gibbs-Donnan inequilibrium • filtration gradient (may decrease/reverse) • Starling laws (oncotic pressure) • elimination by lymph vessels

6. Conventional Assumption (2) “Tissue is a homogenous matrix” The misleading partition coefficient / Binding issues

7. Interstitium Cell Capillary

8. Regulatory View “Distribution studies should be done”

9. Critical Path2003 CDER Report to the Nation We continue ... to extend our long-standing interest in the application of dose-response principlesby viewing drugs and their actions directly at the level of the drug target, rather than indirectly via plasma concentrations

11. Insertion of a microdialysis probe Probe Guide cannula

12. Perfusate Dialysate Interstitium Capillary Cell

16. FDA and „CE“- approved probes

17. µ-dialysis - possible settings Herkner et al. Am J Respir Crit Care Med. 2002 Brunner et al. Br J Clin Pharmacol. 2002

18. Monitoring Chemistry Rembrandt van Rijn (1606-1669), Rijksmuseum, Amsterdam

19. 10 patients with resistant epilepsy requiring implantation of i.c. electrodes. µD-probes were implanted in the amygdala These data provide evidence for activation of the human dopaminergic mesolimbic system during performance of cognitive tasks

22. Drugs: PK-PD

23. Mean ± SD 65% 21%

24. Penetration of Imipenem into the soft tissues of ICU patients Tegeder et al. Clin Pharmacol Ther (2002)

26. Interstitial concentration in vivo (PK)Concentration in culture in vitro (PD)

27. PK PD

28. 500 mg IR bid 250 mg IR qid S. pneumoniae 500 mg MR bid 250 mg MR qid delaPena et al. (2001)

29. PK in Drug Resistant Tumors Zamboni; Cancer Chemother Pharmacol, 1999

31. In vivo PK - In vitro PD PK 5-FU MTX PD Müller et al., Breast Cancer Res Treat 2000

32. Barrier Pertubation Benfeldt et al. Br J Dermatol. 1999

33. Topical pain killers Brunner et al. Brit J Clin Pharmacol 2005

35. Future Concepts Biomarkers in tissues Topical BE Dose finding (PK / PD) “Critical Path” Preclinical screening (CNS)

36. Where are my keys?

37. PET scanner GE Advance Siemens µPET Focus 220

39. 45 min 160min 190min Brunner et al, Antimicrob. Agents & Chemotherapy 2004

40. Time-radioactivity curves after i.v. injection of 700 MBq [18F]ciprofloxacin in healthy volunteers (n=12) Brunner et al, Antimicrob. Agents & Chemotherapy 2004

41. In vivo measuring and modeling of intra- and extracellular drug distribution by combined µD-PET Langer et al, Clin Pharmacol Ther, submitted

42. Conclusions • µD is a safe, reproducible, ethically acceptable and realtively inexpensive technique for studying tissue distribution in humans • µD is a well established technology with standard clinical applications • Most organs can be studied today in appropriate clinical situation • Regulatory documents indicate a rationale for µD • µD affects decision making in clinical R&D and routine practice