Project Summary
Drug-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 Moreover, approximately 50% of the drugs withdrawn for safety reasons from the US market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.
