Monitoring tissue drug levels by microdialysis

Monitoring tissue drug levels by microdialysis
Presentation lecture from: Universitätsklinik für Klinische Pharmakologie
Conventional Assumption
“Blood / Target equilibrium can be taken for granted”
Drug distribution can solely be explained by laws of diffusion

Active Transporters

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

Conventional Assumption

“Tissue is a homogenous matrix”
The misleading partition coefficient / Binding issues
Interstitium
Capillary
Cell
Regulatory View
“Distribution studies should be done”
Critical Path
2003 CDER Report to the Nation

We continue ... to extend our 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

Insertion of a microdialysis probe

Probe
Guide cannula
Interstitium
Capillary
Cell
Perfusate
Dialysate
Interstitial concentration in vivo (PK)
Concentration in culture in vitro (PD)
PK in Drug Resistant Tumors
Future Concepts
* Biomarkers in tissues
* Topical BE
* Dose finding (PK / PD)
* “Critical Path”
* Preclinical screening (CNS)

Where are my keys?
PET scanner
GE Advance
Siemens µPET Focus 220


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

Monitoring tissue drug levels by microdialysis.ppt