3.3 monte toxicogenomics - acmt · aspirin induced asthma. single ‘omic screening isn’t cost...

ADR TOXIC’OMICS

Andrew A. Monte, MD University of Colorado &

Rocky Mountain Poison & Drug Center

DISCLOSURES

Salary partially supported by EMF Research Training Fellowship 2012-2014.

Supported by NIH/NCATS Colorado CTSI grant number UL1 TR001082.

Grant support from the John A. Hartford Foundation.

Grant support from the Dept of EM at UCo.

Opinions discussed are solely my own and do not represent anyone else’s views.

OBJECTIVES

1. History of ADR ‘omics.

2. How we can use single ’omic associations.

3. Systems biology ADR ’omics.

WHY ADRS?

74% of all physician office visits involve drug therapy.

$234.1 billion in prescription costs in 2008.

Repesent approx 6% of hospital admissions.

Easier to characterize phenotypes.

Far more common than overdose.

WE NEED TO OWN THIS.

HISTORICAL TOXICOGENOMICS

510 BC: Pythagoras described the danger of eating fava beans.


1931: First report of inherited difference in response to a chemical (inability to taste phenylthiourea).




1955: Dern reported primaquine induced hemolysis varied by ethnicity in WWII soldiers.




1955: Dern reported primaquine induced hemolysis varied by ethnicity in WWII soldiers.

1957: Arno Motulsky proposed genetic basis as an explanation for individual differences in drug efficacies and adverse reactions.

1960: Peripheral neuropathy associated with metabolism polymorphism, “slow acetylators” for INH.


NAT2 METABOLISM OF INH

72 yo M starting carbamazepine for trigeminal neuralgia.

CARBAMAZEPINE

SHLA-B*1502 associated with SJS/TEN in Asian populations (Taiwan).

HLA-A*3101 hypersensitivity in European populations.

NNT 39 in European, 56 in Japanese, 83 in patients of undetermined descent.

DOES SCREENING MAKE SENSE?

Prevalence of HLA*3101=2-5%

Cost ≈ $400

PPV=79.17%, NPV=63.93% in European populations.

21% of ⊕ tests will not have the ADR. 36% of the ADRs will still have a ⊖ test.

Stop the drug!

NOT ENOUGH APAP?

Can we predict DILI due to therapeutic APAP dosing?

Winnike, et al. used metabolomics at baseline and during 7 days of 4g dosing.

No association with pre-dosing metabolites.

After beginning therapy, metabolites predicted ALT rise prior to standard laboratory testing.

Heard, et al. manuscript in review

SO WHAT?

If they keep taking APAP, LFTs come down!

CYP2C9/VKOR1 and INR.

Statin induced rhabdomyolysis.

Aspirin induced asthma.

Single ‘omic screening isn’t cost effective for clinically

insignificant ADRs!

ABACAVIR

Stevens Johnson Syndrome/TENS

Mortality 10-30%

HLA-B*5701

IDSA recommends ALL patients beginning abacavir be screened.

HLA-B 5701 BINDING GROOVE

Binding groove with abacavir

Binding groove without abacavir

Abacavir

HLA-B 5701 BINDING GROOVE

Binding groove with abacavir

Binding groove without abacavir

Abacavir

Allo-Reactive T Cells

HOW GOOD IS SCREENING?

Hypersensitivity reactions in 5-8% in pre-marketing studies.

PPV=47.9%, NPV 99%.

Screen 100, SJS prevented in 4, no abacavir in 2 that would tolerate.

Bad ADRs with high NPVs, screening makes sense!

‘OMIC ELIMINATION OF SEVERE ADRS

Disulfiram induced liver failure?

Gadolinium induced nephrogenic systemic fibrosis?

Ergotamine induced retroperioneal fibrosis?

Lithium induced SIADH?

Others?

COMMON MISTAKES

Assuming ‘omic associations will be predictive.

Assuming small cohort ‘omic associations will translate to broader populations.

Oversimplification.

‘OMICS LIMITATIONS

DNA Sequence GenomicsHistone

ModificationExon

Intron

RNA Transcriptomics

Environmental Factors Epigenomics

CH3

Methylation

Protein Proteomics

Metabolites Metabolomics

Phenotype Drug response

{

Inhibitory RNA


Genomics: variable penetrance

Epigenomics: environmental differences

Transcriptomics: post-translational modification

Proteomics: variable receptor microenvironments

Metabolomics: adaptation with polygenic response

Phenomics?

PHENOMICS

Unbiased study of large-scale phenotype data.

Identify new biologic pathways.

Can be performed with EMR data!

Demands a systems biology approach.

ToxIC?


Genomics: variable penetrance

Epigenomics: environmental differences

Transcriptomics: post-translational modification

Proteomics: variable receptor microenvironments

Metabolomics: adaptation with polygenic response

Phenomics?

PHENOMICS DATABASES

Consortium for Neuropsychiatric Phenomics: 52 centers, funded by NIH. http://www.phenomics.ucla.edu

US Biobank: Dept of Health Wellcome Trust: 500,000 patients. http://www.ukbiobank.ac.uk

Personal Genome Project: Privately funded. http://www.personalgenomes.org

http://www.phenomics

http://www.ukbiobank

http://www

NSAID HEPATOTOXICITY

Among the most common drugs used worldwide.

Responsible for 10% of drug induced hepatotoxicity.

25% that develop jaundice die.

Severe ADR, commonly used.

‘Omics identified mechanisms: 1.) drug induced cell death, 2.) mitochondrial dysfunction leading to apoptosis 3.) immune reaction.

Can systems biology predict this?



CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5 have been associated with ibuprofen induced hepatotoxicity.

CYP2E1*2, rare variant associated with decreased enzyme function. No association with APAP hepatotoxicity.

UGT2B7*2 associated with diclofenac induced hepatotoxicity.

MnSOD2 associated with nimesulide hepatotoxicity.

TOO COMPLEX!!!

SEPSIS PHENOMICS

Phenomics, proteomics, metabolomics in 150 sepsis patients.

Model: Phenomics + Metabolomics predicted survival in sepsis, accuracy 83.6% for 28 day survival.

Identified pathways previously unrecognized to be physiologically important in survival.

Langley, RJ, et al. Sci Translational Med. 2013.

SEPSIS SYSTEMS BIOLOGY

6 carnitine esters decreased in survivors.

16 carnitine esters and 4 fatty acids elevated in survivors.

Suggests B-oxidation defect in non-survivors.

Sepsis survivors mobilized various energetic substances for oxidative metabolism.

SEPSIS PHENOMICS

Phenomics, proteomics, metabolomics in 150 sepsis patients.

Model: Phenomics + Metabolomics predicted survival in sepsis, accuracy 83.6% for 28 day survival.

Identified pathways previously unrecognized to be physiologically important in survival.

Langley, RJ, et al. Sci Translational Med. 2013.

SYSTEMS BIOLOGY

Genomic +Metabolomic+ Phenomic +

Lots of Patients=

Prediction/Elimination of ADRs

HETEROGENEITY INH ADRS

BRING IT FULL CIRCLE

INH ADRs are perfect for systems biology studies.

Many TB clinics with many patients.

Significant phenotypes gathered, vitals, demographics, physical exam, LFTs, etc.

Prospective study needed.

SUMMARY

Look for single ‘omics association with severe ADRs.

Phenomics may identify common pathways.

Other ‘omics are needed to link them.

Need high throughput integrative analytics.

Dern RJ, Beutler E, Alving AS (1955) The hemolytic effect of primaquine. V. Primaquine sensitivity as a manifestation of a multiple drug sensitivity. J Lab Clin Med 45:30–39. !Motusky AG. (1957) Drug reactions, enzymes, and biochemical genetics. JAMA. 165:835-837. !Evans DA, Manley KA, McKusick VA (1960) Genetic control of isoniazid metabolism in man. Br Med J 2: 485-49. !Mallal S, Phillips E, Carosi G, Molina JM, Workman C, et al. (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358: 568-579. !Chen P, Lin JJ, Lu CS, Ong CT, Hsieh PF, et al. (2011) Carbamazepine induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med 364: 1126-1133. !McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, et al. (2011) HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 364: 1134-1143. !Winnike JH, Li Z, Wright FA, Macdonald JM, O'Connell TM, Watkins PB. Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin Pharmacol Ther 2010;88:45-51. !Parra D, Beckey NP, Stevens GR. The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy 2007;27:675-83. !Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 2008;40:584-91. !Park BL, Kim TH, Kim JH, Bae JS, Pasaje CF, Cheong HS, et al. Genome-wide association study of aspirin-exacerbated respiratory disease in a Korean population. Hum Genet 2013;132:313-21. !Choi GS, Kim JH, Shin YS, Ye YM, Kim SH, Park HS. Eosinophil activation and novel mediators in the aspirin-induced nasal response in AERD. Clin Exp Allergy 2013;43:730-40. !Clarke JD, Hardwick RN, Lake AD, Lickteig AJ, Goedken MJ, Klaassen CD, et al. Synergistic interaction between genetics and disease on pravastatin disposition. J Hepatol 2014. !Houle D, Govindaraju DR, Omholt S. Phenomics: the next challenge. Nat Rev Genet 2010;11:855-66. !Langley RJ, Tsalik EL, van Velkinburgh JC, Glickman SW, Rice BJ, Wang C, et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med 2013;5:195ra95.

References:

3.3 monte toxicogenomics - acmt · aspirin induced asthma. single ‘omic screening isn’t cost...

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