Low Cost Microphysiological System for Improved Pharmacodynamics

DESCRIPTION provided by applicant The high failure rate of drugs in late stage development nearly is a symptom of the inadequacy of pre clinical animal models to accurately predict human biology One of the major reasons drugs fail in the clinic is inaccurate prediction of the therapeutic index which is the dose range where drugs are effective and also not toxic Failure to identify metabolism produced toxicities in preclinical efforts lead to unwelcome and highly expensive surprises in clinical trials and even post marketing of new drugs SciKon has created a serial capillary system in a standard cell culture format that enables researchers to apply drugs to cells in culture using a more in vivo like exposure dynamic In turn a compartmentalized dynamic gradient enables query of each internal serial system for evaluating cellular mechanisms in both a concentration and time resolved manner This proposal describes using this system to query cytotoxicity of drugs to primary human hepatocytes as a function of the real time changes in parent metabolite ratio Our preliminary tests suggests the feasibility of creating a screening assay that distinguishes between whether a test chemical is metabolized to something toxic or not without a priori understanding of a drugsandapos overall metabolism or metabolite ID The aims of this proposal are to quantitate metabolites of common test compounds as a function of both time parent concentration and location within the system and to evaluate a compound training set of drugs with known hepatotoxicity in the clinic as well as the metabolic component of that toxicity Such an assay can be inserted into the drug development pipeline much earlier than current hepatocyte metabolism studies where knowing the metabolite ID is a prerequisite thus reducing the overall cost of drug development and increasing the chances of success in the clinic Furthermore this assay would also apply to chemicals for industrial consumer product cosmetics and foods PUBLIC HEALTH RELEVANCE It is well known that current early stage drug development model systems consisting mainly of static tumor derived cell cultures and rodent animal models poorly predict both efficacy and safety of new therapeutics and commercial chemicals The capability of performing more in vivo like humanized experiments at the benchtop will be more predictive of both drug efficacy and safety and ultimately reduce late stage drug failures The engineered devices at the heart of this proposal accomplish this by creating a more life like environment than standard cell culture consumables and could also be used to create other organ target system multiple organ systems co culture systems and disease models