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

Ended Project Grant Awarded Last action

Award ID
R43GM143980
Recipient
Awarding agency
Obligated
$773,360

Award facts

Assistance listing
93.859 Biomedical Research and Research Training
Completion date
Funding
  • $513,747.23 Federal
  • $259,613.00 Non-federal
Place of performance
Woburn, MA 01801, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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 Moreover, approximately 50% of the drugs withdrawn for safety reasons from the US market between 1999 and 2003 were associated with ddis.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.

Transactions

Action Federal Non-federal Date
Amendment -$5,479 $0
Amendment $0 $0
Amendment $0 $0
Amendment $259,613 $0
Original award $259,613 $259,613

Quick answers

Who received award R43GM143980?

R43GM143980 was awarded to Javelin Biotech Inc. by National Institute of General Medical Sciences (National Institutes of Health) on September 21, 2021.

How much is award R43GM143980 worth?

$773,360 has been obligated on R43GM143980: $513,747 in federal funding and $259,613 in non-federal funding.

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