Microfabricated tool for integrated PK/PD studies of CNS drugs

DESCRIPTION provided by applicant The specific aim of this proposal is to test the feasibility of developing a tool for the simultaneous and continuous measurement of pharmaceutical drug concentrations and electrophysiology recording in the brain for preclinical testing of central nervous system CNS drug candidates The benefits of the proposed tool are three fold improved method of performing in vivo pharmacokinetics PK studies with orders of magnitude improvements in spatial and temporal resolutions over microdialysis the ability to monitor physiological changes at the cellular level for improved understanding of pharmacodynamics PD and the combination of these capabilities in a single tool reduces the number of animals needed for evaluation of a drug candidate The proposed probe will detect lurasidone Latuda and measurements with the proposed probe will be directly compared with traditional PK techniques microdialysis plasma draw and cerebral spinal fluid CSF draw to demonstrate utility in drug development Through our use of aptamers as a detecting mechanism this platform is extensible to monitor most any drug MW Da in the brain Currently microdialysis is used to determine PK of drugs in the brain but it is labor intensive error prone unsuitable for a significant number of drug candidates and has low temporal resolution at minutes per data point Griffin et al Loryan et al Additionally the proposed tool can monitor changes in neuronal firing which is currently used to study the effect of marketed drugs and has been suggested as an effective way to improve the evaluation of drug candidates Tan et al Depoortere et al The proposed tool combines PK and PD studies for improved scientific information and a reduction in required animals and labor We will accomplish our specific aim by Fabricating silicon probes and functionalize with aptamers Selecting an aptamer against psychiatric drug lurasidone Latuda Developing electronics for point of use neural recording and chemical sensing and then Performing in vivo studies with both the proposed sensor and traditional PK methods Success in this Phase I feasibility study will be determined by will be determined by the accurate detection of physiologically relevant lurasidone concentrations and concomitant neural firing recording for hours typical during of a PK study depending on drug half life PUBLIC HEALTH RELEVANCE Psychiatric diseases are the leading cause of healthcare costs at approximately $ billion annually in the US alone Despite the significant need for improved psychiatric drugs many large pharmaceutical companies are reducing or eliminating Randamp D in this area due to the multitude of failures experienced over the last years The goal of this proposal is to develop a tool for the simultaneous recording of neuron electrical activity and measurement of brain drug levels to facilitate psychiatric drug discovery through improved data on the brain response to drugs