A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers.
We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.
Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability.
There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
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Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA. 2001;286:2270–2279.
Pharmacogene Variation Consortium. PharmVar. http://www.PharmVar.org. Accessed 10 September 2018.
Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95:376–382.
Hicks JK, Swen JJ, Gaedigk A. Challenges in CYP2D6 phenotype assignment from genotype data: a critical assessment and call for standardization. Curr Drug Metab. 2014;15:218–232.
Eckhardt K, Li S, Ammon S, et al. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain. 1998;76:27–33.
Lotsch J, Rohrbacher M, Schmidt H, et al. Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation? Pain. 2009;144:119–124.
Poulsen L, Arendt-Nielsen L, Brosen K, Sindrup SH. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther. 1996;60:636–644.
Stamer UM, Musshoff F, Kobilay M, et al. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther. 2007;82:41–47.
Schroth W, Goetz MP, Hamann U, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009;302:1429–1436.
Schroth W, Winter S, Murdter T, et al. Improved prediction of endoxifen metabolism by CYP2D6 genotype in breast cancer patients treated with tamoxifen. Front Pharmacol. 2017;8:582.
Kirchheiner J, Keulen JT, Bauer S, Roots I, Brockmoller J. Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol. 2008;28:78–83.
Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharm J. 2007;7:257–265.
Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351:2827–2831.
Orliaguet G, Hamza J, Couloigner V, et al. A case of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol. Pediatrics. 2015;135:e753–755.
Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98:127–134.
Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102:37–44.
Bell GC, Caudle KE, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron. Clin Pharmacol Ther. 2017;102:213–218.
Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. 2005;102:543–549.
Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol. 2002;20:2805–2811.
Goetz MP, Sangkuhl K, Guchelaar HJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy. Clin Pharmacol Ther. 2018;103:770–777.
Cavallari LH, Beitelshees AL, Blake KV, et al. The IGNITE Pharmacogenetics Working Group: an opportunity for building evidence with pharmacogenetic implementation in a real-world setting. Clin Transl Sci. 2017;10:143–146.
Empey PE, Stevenson JM, Tuteja S, et al. Multisite investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy. Clin Pharmacol Ther. 2018;104:664–674.
Caudle KE, Klein TE, Hoffman JM, et al. Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process. Curr Drug Metab. 2014;15:209–217.
Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte—an update of guidelines. Clin Pharmacol Ther. 2011;89:662–673.
Ramamoorthy A, Flockhart DA, Hosono N, et al. Differential quantification of CYP2D6 gene copy number by four different quantitative real-time PCR assays. Pharmacogenet Genomics. 2010;20:451–454.
Ramamoorthy A, Skaar TC. Gene copy number variations: it is important to determine which allele is affected. Pharmacogenomics. 2011;12:299–301.
Lee, SB, Wheeler, MM, Patterson, K, et al. Stargazer: a software tool for calling star alleles from next-generation sequencing data using CYP2D6 as a model. Genet Med 2018 Jun 6; https://www.nature.com/articles/s41436-018-0054-0 [Epub ahead of print].This article has now been published so please update: Genetics in Medicine volume 21, pages361–372 (2019)
Numanagic I, Malikic S, Pratt VM, et al. Cypiripi: exact genotyping of CYP2D6 using high-throughput sequencing data. Bioinformatics. 2015;31:i27–34.
Storelli F, Matthey A, Lenglet S, et al. Impact of CYP2D6 functional allelic variations on phenoconversion and drug-drug Interactions. Clin Pharmacol Ther. 2018;104:148–157.
Kiss, A, Menus, A, Toth, K, et al. Phenoconversion of CYP2D6 by inhibitors modifies aripiprazole exposure. Eur Arch Psychiatry Clin Neurosci 2019; https://doi.org/10.1007/s00406-018-0975-2. [Epub ahead of print]. PMID: 30604050.
Monte AA, Heard KJ, Campbell J, et al. The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness. Acad Emerg Med. 2014;21:879–885.
Borges S, Desta Z, Jin Y, et al. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. J Clin Pharmacol. 2010;50:450–458.
Wu AH, White MJ, Oh S, Burchard E. The Hawaii clopidogrel lawsuit: the possible effect on clinical laboratory testing. Per Med. 2015;12:179–181.
This work was supported by the National Institutes of Health (NIH) IGNITE Network (http://ignite-genomics.org/) through grants U01HG007269, U01HG007253, U01HG007762, U01HG007775, and U01HG007278. Additional funding provided by the University of Florida and its Clinical Translational Science Institute (NCATS UL1TR000064 and UL1TR001427) for J.A.J., L.H.C., and K.W.W.; NHLBI R0HL092173 and K24HL133373, NCATS UL1TR000165, University of Alabama Birmingham’s Health Service Foundations' General Endowment Fund and Hugh Kaul Personalized Medicine Institute to N.A.L.; NIH Common Fund Program in Health Economics and NHLBI U01HL122904 to J.F.P.; Indiana University Health–Indiana University School of Medicine Strategic Research Initiative to V.M.P. and T.C.S.; NHGRI eMERGE Network U01HG8666 and U01HG006828 (Cincinnati Children’s Hospital Medical Center) and CIDR U01HG004438; University of Minnesota Enhance Comprehensive Pharmacist Services to Improve Patient Health Clinical Research Award to J.R.B.; NCI P30CA076292, Cancer Epidemiology Innovation Funds, DeBartolo Family Personalized Medicine Institute Pilot Research Award in Personalized Medicine, ASHP Research and Education Foundation, and OneOme to J.K.H.; NHGRI U01HG008672 and NCATS UL1TR002243; University of Pennsylvania, Center for Precision Medicine Accelerator Fund to S.T.; NCATS UL1TR001857, an Anonymous Donor, internal funds from the University of Pittsburgh Medical Center, and the Institute for Precision Medicine to P.E.E.; NCBiotech Presidential Grant to GCB; philanthropic donation by T. Denny Sanford IMAGENETICS (Internal Medicine and Genetics) to L.J.H., and NHGRI 3U01HG008701 to A.O.O.
N.A.L. serves as a consultant for Admera Health. V.M.P. is affiliated with the Indiana University School of Medicine Pharmacogenomics Laboratory, which is a fee-for-service clinical laboratory. J.K.H. receives clinical trial support from OneOme and serves as a consultant for Quest Diagnostics. R.A.G. is employed by OneOme, a for-profit genotyping laboratory. L.H.C. has received research funding from Mallinckrodt Pharmaceuticals. The other authors declare no conflicts of interest.
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