DDI-on-a-chip: an optimized liver microphysiological system and microenvironment for complex drug-drug interaction studies

Project SummaryDrug-drug interactions (DDIs), caused by the administration of multiple drugs simultaneously (i.e polypharmacy), can lead to adverse drug reactions (ADRs). The prevalence of polypharmacy-related DDIs among older adults is ~80%. DDI-related ADRs can cause profound clinical effects, either by reducing therapeutic efficacy or increasing the toxicity of drugs. In the United States (US), ADRs are common, causing 1.1% of annual hospital admissions, and expensive with associated annual costs estimated between 30-180 billion dollars. Moreover, approximately 50% of the drugs withdrawn for safety reasons from the US market between 1999 and 2003 were associated with DDIs. This is especially relevant for complex DDIs which include metabolism-transporter interplay, time-dependent and mixed inhibition/induction of drug-metabolizing enzymes (DMEs) and transporters, and metabolite-based inhibition/induction. As DDIs cannot be prevented without comprehensive drug pharmacokinetic (PK) data to guide medication adjustments according to DDI risks, there is a need for carefully planned preclinical and clinical DDI studies during drug development. However, current in vitro preclinical liver PK models, including microphysiological systems (MPSs), suffer from important functional limitations such as expression of a fetal phenotype, low expression levels of drug-metabolizing enzymes and transporters, and rapid phenotypic dedifferentiation (i.e., short-term culture systems). This proposed technology will be especially applicable for drugs with complex DDI liability including time-dependent induction of DMEs and transporters.Javelin’s overall strategy is to develop microphysiological systems (MPSs) optimized for drug metabolism and pharmacokinetics (DMPK) studies including DDIs to be used in combination with our quantitative systems pharmacology (QSP) models to generate more predictive preclinical drug data. This SBIR phase I project will establish the optimal cellular and hepatotropic factor microenvironment to drive long-term, physiologically- relevant expression, and activity of liver DMEs and transporters. The endogenous hepatotropic factors will be selected for their ability to maintain liver cell health and drive the transcription factor signaling networks that regulate DME and transporter gene expression. The hepatotropic factors will be screened using a high- throughput fractional factorial analysis approach and optimized in Javelin’s polycarbonate (i.e., PDMS-free to minimize nonspecific drug adsorption), millifluidic, recirculating MPS engineered for DMPK studies. The resulting medium supplement, “DMPK-optimal” will be the first chemically-defined, xenoprotein-free supplement designed to drive sustained DME and transporter gene expression and activity for DMPK-DDI studies. Javelin’s DMPK- DDI platform will be provided as a low-cost, commercial-available product to pharmaceutical companies interested in generating comprehensive, accurate, human-based PK data to better inform their drug development process and design of first in-human (FIH) trials.Project Narrative Drug-drug interactions (DDIs), a major cause of adverse drug reactions (ADRs), can be mitigated by a thorough understanding of a drug’s pharmacokinetic properties during the preclinical drug development stage. Javelin’s project establishes a physiologically-relevant microenvironment for complex DDI studies composed of primary human liver cells and a chemically-defined, xenoprotein-free hepatotropic factor medium supplement in a PDMS- free, millifluidic, recirculating microphysiological system (MPS). Our novel platform will facilitate the evaluation of a new drug’s comprehensive DDI liability using a human cell-based liver MPS.