Preclinical Development – Chemical
2019 PharmSci 360
The benefits of microdialysis can best be described by its ability to avoid the 'Street Light Effect'. Wikipedia defines the Street Light Effect as a type of observational bias where people only look for whatever they are searching by looking where it is easiest. The search itself may be referred to as a drunkard's search. Taken from an old joke about a drunkard who is searching for something he has lost, the parable is told several ways but typically includes the following details: A policeman sees a drunk man searching for something under a streetlight and asks what the drunk has lost. He says he lost his keys and they both look under the streetlight together. After a few minutes the policeman asks if he is sure he lost them here, and the drunk replies, no, and that he lost them in the park. The policeman asks why he is searching here, and the drunk replies, "this is where the light is."
In the vast majority of pharmacokinetic studies, plasma or serum concentrations are measured under the assumption that they represent good surrogates for drug concentrations at the target site. Furthermore, they are easy to obtain. However, these concentrations may not be the most appropriate parameters to characterize drug exposure at the target site. First, the use of serum concentrations does not consider protein binding when total drug concentrations are used. Furthermore, for most drugs, the site of action is not in the blood but somewhere in the tissue. ‘Total tissue concentrations’ which are derived from tissue biopsies are sometime used to address this issue. However, these concentrations are hybrid numbers which do not reflect the pharmacologically active free drug concentrations at the infection site. Also, the commonly used approach of tissue partition coefficients to quantify tissue concentrations is not acceptable since it implies homogenous distribution of drug in the tissues. Microdialysis allows measurement of unbound drug concentrations in the extravascular space without damaging the surrounding tissue. In this way, differences between total plasma and free extracellular fluid concentrations can be monitored. A number of recent examples will be presented where these unbound concentrations in extracellular fluids in the tissues produce more appropriate pharmacokinetic input parameters for PK/PD models than serum concentrations. This is particularly true if the target site is the extracellular fluid as it is the case for the vast majority of anti-infective agents. Further examples include the use of microdialysis for large molecules with specialized probes, fluid-neutral drug level monitoring in neonates, lung microdialysis in patients with multi-resistant tuberculosis, use of microdialysis in preclinical drug development of drugs to treat leishmaniasis and impetigo as well as methodological issues related to the assessment of topical bioequivalence and unbound intracellular concentrations.