Common use of Discussion and Conclusion Clause in Contracts

Discussion and Conclusion. PK of drugs in the CNS is governed by a combination of CNS system physiology and drug properties. This means that variability in CNS system physiological parameters (condition dependency) may lead to variability of CNS drug PK. Therefore, it is important to explicitly distinguish between system physiology and drug properties, by either changing conditions and investigating the PK of one drug, or investigating the PK of different drugs in the same condition. The currently available predictive approaches are based on total drug plasma and total tissue concentrations at equilibrium (SS), while more recent approaches include, at best, unbound plasma SS concentrations. However, as body processes are based on the interaction with the unbound drug and are time-dependent, it is crucial to measure the unbound drug in each compartment as a function of time (Mastermind Research 2 Approach (MRA)) (4), for which microdialysis has been proven the key technique. Using the MRA, microdialysis will provide lots of valuable data that pave the way towards a generic CNS PBPK model. One microdialysis experiment in a single freely-moving animal can provide a lot of data points, obtained under the same experimental condition of the animal, and thereby revealing the interrelationships of processes. With this microdialysis has already contributed to reduction and refinement in the use of animals. Furthermore, all this information can further be “condensed” into a generic PBPK model, and will thereby help in the reduction in the future use of animals (189). In order to be able to predict CNS drug effects in human, next steps would be the development of a full PBPK CNS drug distribution model, and combining it with target binding kinetics, receptor occupancy and signal transduction (190,191), and including system changes by human disease condition.