Carleton, Bruce C

Groeneweg, Gabriella

Ito, Shinya

Lebel, Denis

Lee, David K

Loucks, Catrina M

Rieder, Michael J

Ross, Colin J

Roy, Carl

English

Scholarship@Western

Western University Scholarship@Western Paediatrics Publications Paediatrics Department 4-1-2020 Pharmacogenomic testing: Enhancing personalized medication use for patients. Catrina M Loucks Gabriella Groeneweg Carl Roy David K Lee Michael J Rieder Department of Paediatrics, the Department of Physiology and Pharmacology, and the Department of Medicine at Western University in London, Ont. See next page for additional authors Follow this and additional works at: https://ir.lib.uwo.ca/paedpub  Part of the Pediatrics Commons Citation of this paper: Loucks, Catrina M; Groeneweg, Gabriella; Roy, Carl; Lee, David K; Rieder, Michael J; Lebel, Denis; Ito, Shinya; Ross, Colin J; and Carleton, Bruce C, "Pharmacogenomic testing: Enhancing personalized medication use for patients." (2020). Paediatrics Publications. 538. https://ir.lib.uwo.ca/paedpub/538 Authors Catrina M Loucks, Gabriella Groeneweg, Carl Roy, David K Lee, Michael J Rieder, Denis Lebel, Shinya Ito, Colin J Ross, and Bruce C Carleton This article is available at Scholarship@Western: https://ir.lib.uwo.ca/paedpub/538 Vol 66: APRIL | AVRIL 2020 | Canadian Family Physician | Le Médecin de famille canadien 241C O M M E N T A R YPharmacogenomic testingEnhancing personalized medication use for patientsCatrina M. Loucks MSc PhD Gabriella Groeneweg MA Carl Roy David K. Lee Michael J. Rieder MD PhD  Denis Lebel MSc FCSHP Shinya Ito MD FRCPC Colin J. Ross MSc PhD Bruce C. Carleton PharmD FCP FISPE A dverse drug reactions (ADRs) are an important clinical problem in modern medicine, sometimes resulting in debilitating and lethal consequences for patients. The burden of ADRs in Canada is under-emphasized owing to most ADRs going unreported.1 However, a 1998 study suggests that ADRs are between the fourth and sixth leading cause of death of hospital-ized patients in the United States.2 Genomic factors play a key role in drug response and contribute substantially to the risk of drug-induced harm. Pharmacogenomics—the determination of the genomic predisposition to a certain response to medication—is a key component in under-standing how to use medication in a safer and more effective manner. Pharmacogenomic testing allows for the detection of genomic factors linked to differences in drug response before treatment, ensuring that the ben-efit of a medication is maximized without the unintended consequences of ADRs. While medication use in clinical practice is already personalized by considering clinical factors that contribute to variable drug responses, phar-macogenomic testing can explain why some patients experience unusual responses to medication and further enhances personalized medication use.The Canadian Pharmacogenomics Network for Drug Safety (CPNDS),3 a group focused on incorporating pharmacogenomics into clinical practice, has identi-fied genomic factors responsible for a number of ADRs, including but not limited to codeine-induced death in breastfed infants,4,5 cisplatin-induced ototoxicity,6,7 and anthracycline-induced cardiotoxicity.8-10 To address these serious ADRs, pharmacogenomic tests have been developed to assess a given patient’s risk of experi-encing an ADR. Clinical practice guidelines have also been created to help clinicians develop better personal-ized therapy plans based on genomic risk.11-13 As more genomic risk factors for ADRs are identified, pharma-cogenomic testing can be optimized to provide better risk-benefit profiling for each patient.The CPNDS and childhood cancer treatmentThe CPNDS has worked to incorporate pharmacoge-nomic testing into childhood cancer treatment deci-sions to reduce the risk of developing ADRs such as anthracycline-induced cardiotoxicity. Anthracyclines, the most frequently used chemotherapeutic drug in Canada, can cause cardiac dysfunction leading to con-gestive heart failure in up to 20% of treated children.13 Based on clinical factors alone, the predicted risk of experiencing this cardiac dysfunction (cardiotoxicity) generally falls in the range of a few percent to an almost 100% chance. Incorporating pharmacogenomic testing helps to better determine a patient’s specific risk before treatment initiation. For instance, in 2 patients with the same diagnosis, one patient’s genomic risk of serious cardiotoxicity might be below 20%, whereas the second patient’s risk might be greater than 80%. Importantly, this ability to quantify pharmacogenomic risk provides a vehicle for patients and their families to dictate the level of risk they are comfortable with, in the paradigm of benefit-risk decision making in their cancer treat-ment. This exemplifies patient-oriented care, where an estimated risk of serious drug-induced cardiotoxicity of less than 20% might be acceptable given the consider-able mortality that accompanies many cancer diagno-ses. However, a predicted risk of drug-induced harm of more than 80% should require discussion of viable alter-natives and pre-emptive preventive therapy. Together, this allows for better profiling for each patient to make informed treatment decisions.Changes to drug labelsThe CPNDS is not the only group focused on finding drug safety solutions through pharmacogenomics. Both the US Clinical Pharmacogenetics Implementation Consortium14 and the Dutch Pharmacogenetics Working Group15 also promote the use of pharmacogenomic infor-mation to enhance clinical decision making. The CPNDS found that the use of codeine for postpartum pain man-agement in mothers with an extra copy of the cyto-chrome P450 2D6 isozyme gene (CYP2D6) can be lethal for their breastfed infants.5 These findings have led to warnings and drug label changes by Health Canada, the US Food and Drug Administration (FDA), the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan. Importantly, this research led to changes in the use of codeine worldwide.11,15,16Pharmacogenomic information to inform clinical practice is included on more than 750 drug labels world-wide (https://www.pharmgkb.org/labels), a number that continues to rise as more pharmacogenomic dis-coveries are made. Currently, the FDA provides phar-macogenomic information on 335 drug labels, while Health Canada has been slower to incorporate such information (included in 105 labels). Given that drugs are used across all medical disciplines, pharmacoge-nomics should be the highest of priorities in both patient 242 Canadian Family Physician | Le Médecin de famille canadien } Vol 66: APRIL | AVRIL 2020COMMENTARY Pharmacogenomic testingcare advancement and federal investment in research. To this end, the FDA facilitates the application of phar-macogenomics in clinical practice through initiatives driven by the Genomics and Targeted Therapy Group. A similar approach could be adopted by Health Canada as a first step toward improving awareness of pharmacoge-nomic information to guide prescribing decisions for Canadian physicians.Integrating pharmacogenomic testing into clinical practiceClinicians who want to integrate pharmacogenomic test-ing into their practices face considerable challenges that limit access. We propose an approach where pharma-cogenomic testing is conducted only when a particular drug is being considered for treatment. The inclusion of only pharmacogenomic variants with clinical relevance, such as those appearing on drug labels or in pharma-cogenomic clinical practice guidelines, or those repli-cated in at least 3 independent populations with strong associations (ie, odds ratios ≥ 3), allows for immediate and evidence-based application to prescribing decisions. Another possible avenue to improve accessibility is a screening approach where comprehensive pharmacoge-nomic information is collected and readily available for future prescribing decisions. This is an attractive strat-egy given the ever increasing affordability of genetic test-ing, and likely represents the future of pharmacogenomic testing,17 but has obstacles for successful implementation. A pharmacogenomic screening approach must adhere to criteria outlined by Wilson and Jungner18 that have been adapted to guide genomic screening approaches,19 with particular emphasis placed on providing strong evi-dence for improved patient outcomes and cost effective-ness through formal program evaluations. Furthermore, deciding which variants should be reported and main-taining an updated list of variants with clinical relevance will require ongoing resources and management of the genomic data collected from screening.Limitations of the health care systemPerceived resource constraints within the Canadian health care system might threaten adoption of phar-macogenomic testing. We therefore propose prioritiz-ing serious ADRs where delays in access to tests put patients at risk of devastating consequences that also represent substantial cost burdens on the health care system. Pharmacogenomic testing for serious ADRs also holds the most promise for cost effectiveness. We have shown that cost savings associated with the preven-tion of one such ADR, anthracycline-induced cardio-toxicity, are predicted to outweigh the costs of testing.20 Specifically, severe cases of anthracycline-induced car-diotoxicity cost more than $1 million owing to the need for heart transplants,20 and incorporation of pharma-cogenomic testing is estimated to save $495 per patient, representing a 5.7% reduction in costs associated with anthracycline-based cancer treatment.20Several parameters must be optimized to improve access for our proposed approach to pharmacogenomic testing, including turnaround time for return of results; integration of sample collection and return of results into linic flow; and availability of pharmacogenomics training. By prioritizing serious ADRs, such as those encountered in childhood cancer treatment, the CPNDS is gaining understanding of how best to deliver pharmacogenomic testing to suit the needs of physicians, patients, and families, while also assessing the effect of such testing on the Canadian health care system by formally evaluat-ing cost effectiveness. Importantly, lessons learned from these experiences will help family physicians incorpo-rate pharmacogenomic testing for additional serious ADRs in the future. In particular, clinically relevant phar-macogenomic information informs the risk of experi-encing the many serious ADRs encountered as a result of analgesics (eg, codeine- or tramadol-induced central nervous system depression or death), antibiotics (eg, rifampin-isoniazid-pyrazinamide–induced liver injury), and psychotropic medications (eg, carbamazepine- or phenytoin-induced skin reactions) that are commonly prescribed by family physicians. Given that these seri-ous ADRs are typically rare, ordering pharmacogenomic testing will allow family physicians to continue prescrib-ing highly effective drugs with well understood safety profiles in patients determined to be at low risk of expe-riencing ADRs, while choosing alternative drugs and avoiding potential harm in patients at high risk.ConclusionUltimately, increasing accessibility to pharmacogenomic tests means better profiling risks of therapy before ther-apy begins and provides the potential to drastically affect the use of medication by making it safer, more effective, and personalized. It is an ethical responsibility for all of us—clinicians, hospital administrators, and policy mak-ers—to provide access to this service to all Canadian families to help prevent serious ADRs when battling dis-eases and illnesses that require medication.   Dr Loucks is a postdoctoral fellow in the Department of Pediatrics at the University of British Columbia in Vancouver. Ms Groeneweg is Program Manager in the Department of Pediatrics at the University of British Columbia. Mr Roy was President and Chief Executive Officer of the Provincial Health Services Authority in Vancouver. Mr Lee is Chief Regulatory Officer in the Health Products and Food Branch at Health Canada in Ottawa, Ont. Dr Rieder is Professor in the Department of Paediatrics, the Department of Physiology and Pharmacology, and the Department of Medicine at Western University in London, Ont. Dr Lebel is a pharmacist at the Centre Hospitalier Universitaire Sainte-Justine in Montreal, Que. Dr Ito is Professor in the Department of Paediatrics at the University of Toronto in Ontario. Dr Ross is Assistant Professor in the Faculty of Pharmaceutical Sciences at the University of British Columbia. Dr Carleton is Professor and Chair in the Division of Translational Therapeutics in the Department of Pediatrics at the University of British Columbia.AcknowledgmentThis work was recently funded through a Genome Canada grant. Funding associated with this submission includes a BC Children’s Hospital Research Institute Bertram Hoffmeister Postdoctoral Fellowship (C.M.L.), a Michael Smith Foundation for Health Research scholar award (C.J.R.), and a Canadian Institutes of Health Research–GlaxoSmithKline Endowed Chair in Paediatric Clinical Pharmacology appointment (M.J.R.). Additionally, the Canadian Pharmacogenomics Network for Drug Safety, of Vol 66: APRIL | AVRIL 2020 | Canadian Family Physician | Le Médecin de famille canadien 243Pharmacogenomic testing COMMENTARYwhich the authors are members, receives funding from Genome Canada, Genome British Columbia, Canadian Institutes of Health Research, the Provincial Health Services Authority, the BC Children’s Hospital Foundation, and matching funds for a federal Genome Canada GAPP grant from Dynacare Laboratories.Competing interestsNone declaredCorrespondenceDr Bruce Carleton; e-mail bcarleton@popi.ubc.caThe opinions expressed in commentaries are those of the authors. Publication does not imply endorsement by the College of Family Physicians of Canada.References1. Mittmann N, Knowles SR, Gomez M, Fish JS, Cartotto R, Shear NH. Evaluation of the extent of under-reporting of serious adverse drug reactions: the case of toxic epidermal necrolysis. Drug Saf 2004;27(7):477-87.2. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospital-ized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.3. Carleton B, Poole R, Smith M, Leeder J, Ghannadan R, Ross C, et al. Adverse drug reaction active surveillance: developing a national network in Canada’s children’s hospitals. Pharmacoepidemiol Drug Saf 2009;18(8):713-21.4. Sistonen J, Madadi P, Ross CJ, Yazdanpanah M, Lee JW, Landsmeer ML, et al. Predic-tion of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers. Clin Pharmacol Ther 2012;91(4):692-9. Epub 2012 Mar 7.5. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of mor-phine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;368(9536):704.6. Ross CJ, Katzov-Eckert H, Dubé MP, Brooks B, Rassekh SR, Barhdadi A, et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat Genet 2009;41(12):1345-9. Epub 2009 Nov 8. Erratum in: Nat Genet 2013;45(5):578.7. Pussegoda K, Ross CJ, Visscher H, Yazdanpanah M, Brooks B, Rassekh SR, et al. Repli-cation of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children. Clin Pharmacol Ther 2013;94(2):243-51. Epub 2013 Apr 10.8. Aminkeng F, Bhavsar AP, Visscher H, Rassekh SR, Li Y, Lee JW, et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet 2015;47(9):1079-84. Epub 2015 Aug 3.9. Visscher H, Ross CJ, Rassekh SR, Sandor GS, Caron HN, van Dalen EC, et al. Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. Pediatr Blood Cancer 2013;60(8):1375-81. Epub 2013 Feb 25.10. Visscher H, Ross CJ, Rassekh SR, Barhdadi A, Dubé MP, Al-Saloos H, et al. Pharma-cogenomic prediction of anthracycline-induced cardiotoxicity in children. Clin Oncol 2012;30(13):1422-8. Epub 2011 Sep 6.11. Madadi P, Amstutz U, Rieder M, Ito S, Fung V, Hwang S, et al. Clinical practice guide-line: CYP2D6 genotyping for safe and efficacious codeine therapy. J Popul Ther Clin Pharmacol 2013;20(3):e369-96. Epub 2013 Nov 6.12. Lee JW, Pussegoda K, Rassekh SR, Monzon JG, Liu G, Hwang S, et al. Clinical practice recommendations for the management and prevention of cisplatin-induced hear-ing loss using pharmacogenetic markers. Ther Drug Monit 2016;38(4):423-31.13. Aminkeng F, Ross CJ, Rassekh SR, Hwang S, Rieder MJ, Bhavsar AP, et al. Recom-mendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity. Br J Clin Pharmacol 2016;82(3):683-95. Epub 2016 Jun 30. 14. Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clin Pharmacol Ther 2011;89(3):464-7. Epub 2011 Jan 26. 15. Swen JJ, Wilting I, de Goede AL, Grandia L, Mulder H, Touw DJ, et al. Pharmacoge-netics: from bench to byte. Clin Pharmacol Ther 2008;83(5):781-7. Epub 2008 Feb 6. Erratum in: Clin Pharmacol Ther 2008;84(1):175. 16. Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, et al. Clini-cal Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2012;91(2):321-6.17. Weinshilboum RM, Wang L. Pharmacogenomics: precision medicine and drug response. Mayo Clin Proc 2017;92(11):1711-22. Epub 2017 Nov 1. 18. Wilson JMG, Jungner G. Principles and practice of screening for disease. Public Health Papers 34. Geneva, Switz: World Health Organization; 1968. Available from: http://whqlibdoc.who.int/php/WHO_PHP_34.pdf. Accessed 2020 Mar 6.19. Andermann A, Blancquaert I, Beauchamp S, Déry V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ 2008;86(4):317-9.20. Dionne F, Aminkeng F, Bhavsar AP, Groeneweg G, Smith A, Visscher H, et al. An initial health economic evaluation of pharmacogenomic testing in patients treated for child-hood cancer with anthracyclines. Pediatr Blood Cancer 2018;65(3). Epub 2017 Dec 22.This article has been peer reviewed. Can Fam Physician 2020;66:241-3Cet article se trouve aussi en français à la page 247.

Pharmacogenomic testing: Enhancing personalized medication use for patients.

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Pharmacogenomic testing: Enhancing personalized medication use for patients.

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