Pharmacogenetics: Where Is It Headed?
When the Human Genome Project (HGP) was completed in 2001, it was anticipated that within the ensuing 10 years, (ie, by 2011) genetic information would lead to advances in targeted drug discovery and prediction of drug responsiveness, and that by 2020, the pharmacogenomics approach for predicting drug responsiveness would become standard practice.1
A recent article, "Pharmacogenetics in Clinical Practice: How Far Have We Come, and Where Are We Going?" analyzes how close we are to fulfilling these expectations.1
Genetic-Guided Drug Discovery and Development
There have been "notable advances in the use of genomic information to guide drug discovery and development, particularly in the area of cancer," as well as two additional drugs (one for CCR5-tropic HIV and one for cystic fibrosis patients with the CFTRG551D mutation).1
The author suggests that drugs to treat cancer and infectious diseases may represent the "low-hanging fruit for genetically informed drug discovery," as most of these drugs are highly focused on targeted mechanisms, further aided by genomics and systems biology approaches.2
By contrast, common, complex diseases have "environmental and multiple genetic influences, with each gene contributing in smaller ways." Thus, the author notes, the targeted approach focusing on specific mutations may be less suited for chronic disease treatments.
However, genes identified through genome-wide association may still identify important protein targets. For example, polymorphisms in CETP and PCSK9 are associated with elevated high-density lipoprotein (HDL) and low levels of low-density lipoprotein (LDL) respectively.3,4 Drugs targeting these proteins (rather than the genetic polymorphisms) are promising agents in potentially raising HDL and lowering LDL.5,6
The author suggests that "the next decade will provide clarity about whether genetic/genomic-guided approaches to drug discovery and development will largely remain within therapies for cancer and infectious diseases, or will also become a common, widespread approach to the development of drugs for common diseases."
Pharmacogenetics to Guide Drug Therapy Decisions in the Clinical Setting
There have been substantial advances in discoveries of genetic associations with drug response.1 The U.S. Food and Drug Administration (FDA) has been aggressive in providing genetic labeling on new drugs,1 and the Clinical Pharmacogenic Implementation Consortium (CPIC), formed in 2009, provides comprehensive reviews and guidelines on the clinical use of pharmacogenetics information. Eight currently published guidelines focus on commonly used agents such as clopidogrel7 or codeine.8
In today's clinical setting, it is "well accepted" to test for genetic mutation or downstream protein expression prior to the use of certain therapies.1 The author attributes this to strong data pointing to poor efficacy, or absence of data pointing to good efficacy, in individuals lacking the genetic mutation, as well as endorsement by the CPIC. However, the author notes, "use of pharmacogenetics data in clinical practice is still far from the norm."
Barriers and Challenges to Clinical Implementation
The author lists barriers to the clinical implementation of pharmacogenetics, including:
- Test-related concerns, as tests must be performed in a regulated clinical laboratory, often with rapid turnaround time, at high cost, and with potential lack of reimbursement.
- Knowledge barriers, which necessitate increased genetics education among medical, pharmacy, and other health professionals. The author notes that these educational efforts may be insufficient and advises the use of clinical decision support tools, which offer clear guidance on therapeutic options, based on genotype.
- Evidence barriers—ie, controversies over the level of evidence required for clinical implementation of pharmacogenetics. For example, recent consensus guidelines for warfarin and clopidogrel recommend against routine pharmacogenetics testing, based on lack of evidence of benefit.9,10,11 However, the author anticipates "increasing clarity regarding the evidentiary standards for clinical implementation of pharmacogenetics" in the coming years.
- Ethical, legal, and social implications of testing (eg, concerns about inclusion of genetic information in the medical record, with potential for genetic discrimination, or questions about sharing pharmacogenetics findings with family members) remain significant barriers.
Since 2001, there have been "substantial advances in pharmacogenetics," including drugs developed under a genetically targeted approach (mostly for cancer), and advances in understanding the genetic determinants of drug response, which may lead to more frequent use of pharmacogenetics data to inform drug therapy decisions.
The author concludes that "it is anticipated that the next five to 10 years will define the importance of pharmacogenetics in the clinical setting" and that "all signs point to continued advances, such that the projection of clinical use of pharmacogenetics data in 2020 will occur."
1. Johnson JA. Pharmacogenetics in clinical practice: how far have we come and where are we going? Pharmacogenomics. 2013;14(7):835-843.
2. Rubin EH, Gilliland DG. Drug development and clinical trials--the path to an approved cancer drug. Nat Rev Clin Oncol. 2012;9(4):2152-2122.
3. Asselbergs FW, Guo Y, van Iperen EP, et al. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. Am J Hum Genet. 2012;91(5):823-838.
4. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161-165.
5. Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306(19):2099-2109.
6. Do RQ, Vogel RA, Schwartz GG. PCSK9 Inhibitors: potential in cardiovascular therapeutics. Curr Cardiol Rep. 2013;15(3):345.
7. Scott SA, Sangkuhl K, Gardner EE, et al. Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther. 2011;90(2):328-332.
8. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. 2012;91(2):321-326.
9. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-84S.
10. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):2574-2609.
11. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;57(19):e215-367.