Speed and Safety in Drug Discovery  Discussion meeting 26 November 2008 9am – 5pm The Royal Society 6-9 Carlton House Terrace, London SW1Y 5AG
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Speakers' Abstracts

Prof Markus Müller
Vienna Medical University, Allgemeines Krankenhaus, Währinger Gürtel 18–20, A-1090 Vienna, Austria.

Monitoring tissue drug levels by microdialysis

The in vivo assessment of drug distribution, in particular, has long been treated as a "forgotten relative" of pharmacokinetics, mainly due to a lack of appropriate methodology. Research was long restricted to drug concentration measurements from biological specimens that are relatively easy to obtain or to indirect modeling of tissue concentrations from plasma concentration curves, which in most cases served as surrogates for true target site concentrations. Data obtained by these approaches, however, have caused considerable confusion about drug distribution and target site delivery, as their interpretation was flawed by several misconceptions, i.e. the lack of physiological input in Pk models, the erroneous view that tissue is a uniform matrix, and the notion that the entire drug fraction present in various tissue spaces exerts pharmacologic activity. Today drug distribution to the well defined tissue compartment „interstitial space fluid“, i.e. the biophase for many drugs can be measured relatively cheaply, minimally invasively and reproducibly with microdialysis (μD).

Besides other documents, and in light of the critical path initiative, the CDER report to the nation 2003 indicated a need for tools that enable the measurement of tissue concentrations by stating that CDER continues to extend its “long-standing interest in the application of dose-response principles by viewing drugs and their actions directly at the level of the drug target, rather than indirectly via plasma concentrations”. Because μD measures unbound, i.e. pharmacologically active drug concentrations in the interstitium has led to a reappraisal of concepts of “tissue­penetration” by antimicrobial drugs. ΜD data indicate that in healthy people interstitial concentrations of beta­lactams are in the range of free serum concentrations, whereas interstitial levels of chinolones and macrolides are considerably lower than those predicted from biopsies. For several conditions, notably septicaemia and septic shock, tissue concentrations of antibiotics such as piperacillin may be subinhibitory even though effective concentrations are attained in serum. In Oncology, µD-studies in patients with breast cancer and melanoma revealed no association between serum concentrations of anticancer drugs and tumour exposure to the drugs. However, there is preliminary evidence that the concentrations of cytotoxic drugs in a tumour may correlate with response to chemotherapy. These findings cast doubt on the use of serum drug concentrations to predict response and corroborate previous findings of a high variability of drug penetration into tumours. Topical application of drugs is an attractive way to circumvent systemic side effects, but it is often not clear whether adequate drug concentrations are reached in the tissue. μD permits this issue to be addressed and could be used to identify formulations and doses of topically applied non­steroidal anti­ inflammatory drugs that produce effective local concentrations. The use of μD in topical drug research may thus lead to a critical reappraisal of cost benefit ratios of topically administered drugs.

In conclusion, 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 and can be applied to most organs in appropriate clinical situation. Regulatory documents indicate a rationale for µD which affects decision making in clinical R&D and routine practice.

 

  1. Müller M. Science, medicine and the future: microdialysis. BMJ 324: 588-591 (2002)
  2. Chaurasia CS et al. AAPS-FDA Workshop White paper: Microdialysis principles, application and regulatory perspectives. J Clin Pharmacol 47:589-603 (2007)
  3. Müller M. Microdialysis in clinical drug delivery studies. Adv Drug Deliv Rev 45: 255-269 (2000)
  4. Eichler HG and M.Müller: Drug distribution – the forgotten relative of clinical pharmacokinetics. Clin Pharmacokinet 34 (2): 95-99 (1998)
  5. Brunner M, Derendorf H and Müller M. Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of antiinfective drugs. CurrOpinion Pharmacol 5(5):495-9 (2005).