PHARMACOGENOMIC INVESTIGATION OF ADVERSE DRUG REACTIONS (ADRS): THE ADR PRIORITIZATION TOOL, APT

Main Article Content

Kaitlyn Shaw
Ursula Amstutz
Lucila Castro-Pastrana
Tenneille T Loo
Colin J Ross
Shinya Ito
Michael J Rieder
Maurica Maher
Stuart MacLeod
Gideon Koren
Michael R Hayden
Bruce C Carleton

Keywords

Pharmacogenomics, adverse drug reactions, ADR study prioritization

Abstract

Background
The impact of genetic factors on the risk of adverse drug reactions (ADRs) is being increasingly recognized as clinically important. ADR Prioritization Tool (APT) was developed to facilitate the prioritization of drugs and their associated ADRs for future pharmacogenomic studies.



Objectives
To describe a novel tool developed for the prioritization of pharmacogenomic investigation of ADRs and discuss the impact of specific scoring criteria.



Methods
APT scores were based on 25 key scientific and feasibility criteria relevant for clinical research evaluating the genetic basis of ADRs, with a maximum possible score of 60 points. The tool was independently applied to five ADRs (warfarin-induced bleeding/thrombosis, cisplatin-induced ototoxicity, methotrexate-induced neutropenia, carbamazepine-induced Stevens-Johnson syndrome, and abacavirinduced hypersensitivity) by two researchers. Scores were compared using the intraclass correlation coefficient (ICC) to determine level of agreement.



Results
Overall scores for target ADRs ranged from 19.5 to 44 points (33-73% of maximum possible score). Cisplatin-induced ototoxicity, a frequent and severe ADR, received the highest score (44). Lower scores were obtained for abacavir-induced hypersensitivity (19.5) and methotrexate-induced neutropenia (28). High agreement was observed between the scientific, feasibility, and total scores from two reviewers (ICC values = 0.895, 0.980, and 0.983, respectively).



Conclusion
Application of APT enables simple and direct comparison of potential study targets for research groups embarking on pharmacogenomic investigation of ADRs. Research teams will be able to identify which study targets are best suited for their research environment and discern how to optimize resource allocation for successful discovery and replication of clinically relevant biomarkers.

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References

1. U.S. Department of Energy Genome Programs. Human Genome Project (January 7, 2013) http://genomics.energy.gov (July 31, 2012).
2. Meisel C, Gerloff T, Kirchheiner J, et al. Implications of pharmacogenetics for individualizing drug treatment and for study design. J Mol Med 2003;81(3):154-67.
3. Ross CJD, Katzov-Eckert H, Dube MP, et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat Genet 2009;41(12):1345-U118.
4. Visscher H, Ross CJ, Rassekh SR, et al. Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children. J Clin Oncol 2012;30(13):1422-28.
5. Sistonen J, Madadi P, Ross CJ, et al. Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers. Clin Pharmacol
Ther 2012;91(4):692-9.
6. Chung WH, Hung SI, Hong HS,et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428(6982):486.
7. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLADR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359(9308):727-32.
8. Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002;359(9312):1121-2.
9. Bates DW, Cullen DJ, Laird N, et al. Incidence of Adverse Drug Events and Potential Adverse Drug Events - Implications for Prevention. J Am Med Assoc 1995; 274(1):29-34.
10. Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP. Adverse drug events in hospitalized patients - Excess length of stay, extra costs, and attributable mortality. J Am Med Assoc 1997;277(4):301-6.
11. Lunetta KL. Genetic association studies. Circulation 2008;118(1):96-101.
12. Sung NS, Crowley WF, Genel M, et al. Central challenges facing the national clinical research enterprise. J Am Med Assoc 2003;289(10):1278-87.
13. Hewitt RE. Biobanking: the foundation of personalized medicine. Curr Opin Oncol 2011;23(1):112-9.
14. Common Terminology Criteria for Adverse Events v4.0 (CTCAE) (June 14, 2010). http://evs.nci.nih.gov/ftp1/CTCAE/About.html.
15. Tracy TS, Venkataramanan R, Glover DD, Caritis SN. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A activity) during pregnancy. Am J Obstet
Gynecol 2005;192(2):633-9.
16. Carleton BC, Poole RL, Smith MA, et al. Adverse drug reaction active surveillance: developing a national network in Canada's children's hospitals. Pharmacoepidemiol Drug Saf 2009;18(8):713-21.
17. R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing 2011.
18. Matthias G, Lemon J, Singh I. irr: Various Coefficients of Interrater Reliability and Agreement. R package version 0.83 2010.
19. Barendse W. The effect of measurement error phenotypes on genome wide association studies. BMC Genomics 2011;12.
20. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005;352(22):2285-93.
21. Aithal GP, Day CP, Kesteven PJL, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999;353(9154):717-9.
22. Yang L, Ge W, Yu F, Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement--a systematic review and meta analysis. Thromb Res 2010;125(4):e159-66.
23. Lindh JD, Holm L, Andersson ML, Rane A. Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis. Eur J Clin Pharmacol 2009;65(4):365-75.
24. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011;364(12):1134-43.

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