Broadly, we will bracket our hypothesis driven studies in 5 model systems – yeast, mammalian cells, zebrafish, mice and humans – with two distinct sets of clinical studies in large numbers of people. The first will be exploratory and hypothesis generating. In these studies, outlined in our Population Pharmacology Core, we will seek to verify unexpected correlates of drug exposure and risk that may emerge from our deep phenotyping studies of smaller numbers of healthy volunteers that will be performed under highly controlled circumstances and are described in our Human Biology Cores. Will such signatures of drug effect be still detectable in the “real world”? The second set of clinical investigations at scale will be a series of hypothesis driven studies. These will be framed by the outcome of (i) our initial observational studies and (ii) our translational studies, manipulating the prostaglandin system and integrating data using systems approaches to identify potential genomic susceptibilities and biomarkers of efficacy and risk. Because these will be developed by careful approaches to discovery over time, the hypothesis testing will most likely occur in the second 5 year funding period.
A central “glue” component of this program is that we will harness our various areas of expertise by performing a common, integrative experiment, as outlined in our Systems Pharmacology Core, transcending our five model systems and assessing the impact of two NSAIDs – celecoxib and naproxen – at standardized doses and time points and assess GEPLIMM outputs, relating them to measures of drug exposure across the systems.
These drugs are selected due to their common clinical use and their varied selectivity for COX-2. Celecoxib, designed to inhibit selectively COX-2 remains on the US market. Celecoxib has been demonstrated to elevate CV risk in randomized controlled trials (RCTs) (1). Naproxen, an older drug, inhibits both COX-1 and COX-2 and is the only NSAID aside from aspirin that attains in some individuals – due to an extended half life - sustained and functional inhibition of platelet COX-1 across a typical dosing interval (1). The best available, albeit inconclusive, evidence suggests that it is the least cardiotoxic amongst the NSAIDs (1). Thus, these pharmacological probes allow us to investigate the relative importance of selectivity for inhibition of COX-2 in NSAID action once these drugs are dosed to similar potency. The translational studies will extend throughout the funding period and will generate information that will iteratively refine the design of the second of our series of clinical studies performed at scale. This approach will render feasible within a ten year period the delivery of an answer to our “big question” and set the stage for application of a similar paradigm to other drug classes. Encouragingly, such translational studies – initially lipidomic analyses of drug response in healthy volunteers followed by proof of concept studies in diverse model systems and eventually observational studies and placebo controlled trials predicted and explained mechanistically the CV risk from NSAIDs (1).
Thus, in this first funding cycle of this GLUE grant our emphasis will be placed on the generation and testing of hypotheses related to the identification of (i) individual factors that influence and (ii) network responses that reflect NSAID efficacy and risk. The strategy will depend on experimentation, data curation, validation and integration and then the iterative development of models in our Systems, Modeling and Computation Core to generate hypotheses relevant to variability in drug response.