Improving prediction of drug action Drugs are variably effective and cause adverse drug reactions (ADRs). ADRs extract major costs at individual and societal levels, leading to medication non-compliance, inefficacy, toxicity, hospitalization, and death. They can be on-target or off-target, they occur across the spectrum of therapies, and they have an important, and increasing, impact not only on the way in which drugs are used in individual subjects and across healthcare systems but on the way in which new candidate molecules are developed. This Center of Excellence has as its major goal the elucidation of new mechanisms underlying variability in drug action and ADRs. We bring to this effort a unique collection of new tools and resources that enable us to confidently predict rapid development of entirely new classes of knowledge that will be a paradigm-shift from current norms of slow, incremental progress. Project 1 focuses on QT interval prolongation by drugs, a major cause for drug relabeling and withdrawals over the last two decades. Conventional wisdom has focused on the drug block of the HERG channel as the major mechanism, but we present compelling data that other pathways play a critical role. We will integrate the results of our previous genomic, molecular, cellular, and clinical studies in the field, exciting new data on the role of P3 kinase in this ADR, and the capability of generating cardiomyocytes from individuals whose drug response phenotypes we have established to develop new paradigms to identity risk in new drug candidates and across patient populations. Project 2 focuses on immunologically-mediated ADRs, and uses a unique resource of cells and DNA from patients with drug hypersensitivity or drug tolerance in the face of a specific HLA risk allele to define associations between HLA alleles, specific T-cell receptor usage and severe T-cell mediated drug hypersensitivity. Our goal is to test a new heterologous immunity model of drug hypersensitivity to explain this phenotypic variability and inform the development of new predictive models. Project 3 applies the new technology of phenome-wide scanning that we have pioneered to a large cohort of subjects with genomic and longitudinal electronic medical record data to broadly repurpose drugs for new indications and refine prediction of long QT-related, HLA-related, and other ADRs. The results of work in the Center will thus advance our long term goal of improving the outcome of drug therapy by reducing the burden of ADRs, improving prediction in an individual subject, repurposing available drugs, and providing new tools to the drug development process to reduce ADR risk.

Public Health Relevance

Drugs are often ineffective and adverse drug reactions (ADRs) cause medication non-compliance, toxicity, hospitalization, and death. ADRs can be on-target or off-target, they occur across the spectrum of therapies, and they have an important, and increasing, impact not only on the way in which drugs are used in individual subjects but on the way in which new candidate molecules are developed. This Center of Excellence has as its major goal the elucidation of new mechanisms underlying variable drug actions with the goals of improving therapy for individual subjects, providing new models for evaluating risk of new candidate molecules, and repurposing existing drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM115305-06
Application #
9745641
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Long, Rochelle M
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Greninger, Alexander L; Knudsen, Giselle M; Roychoudhury, Pavitra et al. (2018) Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6. BMC Genomics 19:204
Karnes, Jason H; Miller, Matthew A; White, Katie D et al. (2018) Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions. Annu Rev Pharmacol Toxicol :
Bastarache, Lisa; Hughey, Jacob J; Hebbring, Scott et al. (2018) Phenotype risk scores identify patients with unrecognized Mendelian disease patterns. Science 359:1233-1239
Kim, Whan B; Worley, Brandon; Holmes, James et al. (2018) Minimal clinically important differences for measures of treatment efficacy in Stevens-Johnson syndrome and toxic epidermal necrolysis. J Am Acad Dermatol 79:1150-1152
Kroncke, Brett M; Yang, Tao; Kannankeril, Prince et al. (2018) Exploiting ion channel structure to assess rare variant pathogenicity. Heart Rhythm 15:890-894
Redwood, A J; Pavlos, R K; White, K D et al. (2018) HLAs: Key regulators of T-cell-mediated drug hypersensitivity. HLA 91:3-16
Robinson, Jamie R; Denny, Joshua C; Roden, Dan M et al. (2018) Genome-wide and Phenome-wide Approaches to Understand Variable Drug Actions in Electronic Health Records. Clin Transl Sci 11:112-122
Greninger, Alexander L; Roychoudhury, Pavitra; Makhsous, Negar et al. (2018) Copy Number Heterogeneity, Large Origin Tandem Repeats, and Interspecies Recombination in Human Herpesvirus 6A (HHV-6A) and HHV-6B Reference Strains. J Virol 92:
Trubiano, Jason A; Grayson, M Lindsay; Phillips, Elizabeth J et al. (2018) Antibiotic allergy testing improves antibiotic appropriateness in patients with cancer. J Antimicrob Chemother 73:3209-3211
Galligan, James J; Wepy, James A; Streeter, Matthew D et al. (2018) Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks. Proc Natl Acad Sci U S A 115:9228-9233

Showing the most recent 10 out of 114 publications