In vivo monitoring of brain pharmacokinetics and pharmacodynamics with cerebral open flow microperfusion

Abstract

In vivo investigation of brain pharmacokinetics and pharmacodynamics (PK/PD) is an integral part of neurological drug development. However, drugs intended to act in the brain may reach it at very low concentrations due to the protective effect of the blood-brain barrier (BBB). Consequently, very sensitive measurement methods are required to investigate PK/PD of drugs in the brain. Also, these methods must be capable of continuously assessing cerebral drug concentrations with verifiable intact BBB, as disrupted BBB may lead to compound efflux from blood into brain and to biased results. To date, only a few techniques are available that can sensitively measure drug concentrations in the brain over time; one of which is cerebral open flow microperfusion (cOFM). cOFM's key features are that it enables measurement of cerebral compound concentrations with intact BBB, induces only minor tissue reactions, and that no scar formation occurs around the probe. The membrane-free cOFM probes collect diluted cerebral interstitial fluid (ISF) samples that are containing the whole molecule spectrum of the ISF. Further, combining cOFM with an in vivo calibration protocol (e.g. Zero Flow Rate) enables absolute quantification of compounds in cerebral ISF. In general, three critical aspects have to be considered when measuring cerebral drug concentrations and recording PK/ PD profiles with cOFM: (a) the BBB integrity during sampling, (b) the status of the brain tissue next to the cOFM probe during sampling, and (c) the strategy to absolutely quantify drugs in cerebral ISF. This work aims to review recent applications of cOFM for PK/PD assessment with a special focus on these critical aspects. K E Y W O R D S blood-brain barrier, cerebral open flow microperfusion (cOFM), neurological drug development, pharmacodynamics, pharmacokinetics Thomas Altendorfer-Kroath and Joanna Hummer authors contributed equally to this study.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Comparative Study of Dermal Pharmacokinetics Between Topical Drugs Using Open Flow Microperfusion in a Pig Model

“…As a minimally-invasive and well-tolerable method, it has been successfully utilized in human clinical studies to investigate biomarkers and drug PK-PD in target tissues in healthy subjects and patients [ 19 – 24 ]. In preclinical research it has been utilized for the study of novel compounds at their targets in animal brain [ 25 – 27 ] and in animal peripheral tissues in vivo [ 28 – 31 ] as well as in explanted human and animal tissues ex vivo [ 32 , 33 ]. The probes for dermal OFM (dOFM probes) provide access to dermal interstitial fluid (dISF) for the continuous in vivo assessment of drugs and biomarker concentrations in humans and animals [ 17 , 28 , 34 – 38 ].…”