Toxicogenomics and Drug Monitoring

Biography

Biography: Murat Cirit

Abstract

Drug development continues to suffer high attrition rates due to unexpected toxicity and lack of efficacy. Too often, preclinical studies using animal models have provided unreliable predictions of human response in late-stage clinical trials. The Microphysiological Systems (MPS) programs, funded by the Defense Advanced Research Projects Agency (DARPA) and National Institutes of Health (NIH), aim to develop in vitro platforms with multiple interacting microphysiological systems to mimic human physiology. The goal is to obtain, in the preclinical setting, more robust drug efficacy, toxicity and pharmacokinetic predictions that can be translated to humans. The interest in MPS development has taken advantage of tissue engineering efforts to also create better in vitro models of human tissues that capture 3D physiology for use in applications ranging from drug development to disease pathophysiology studies. Furthermore these efforts, with contributions from both traditional in vitro model and tissue engineering directions, requires an integration of design principles from molecular to macroscopic length scales, using mechanism-based mathematical models of cell behavior in response to therapeutic drugs. These Systems Pharmacology approaches offer new insight into design of experiments, data interpretation and organ-specific responses, which can be translated to in vivo responses, such as drug efficacy and toxicity. For example, ADME, pharmacodynamic and toxicodynamic properties of a drug can be experimentally investigated in multi-MPS platforms under various physiological conditions. Complex experimental results can be interpreted using mechanistic pharmacokinetic & pharmacodynamics (PK/PD) models allowing us to predict clinical outcomes more accurately than existing preclinical animal models.