Pharmacogenetics – Tailoring your product to fit the genes
By Carron Sher, M.D.
Senior Clinical Research Physician
John received anti-malarial therapy and developed severe hemolytic anemia. He was diagnosed as having G6PD deficiency. Sally was started on warfarin and there was a problem in achieving the desired therapeutic response. She was diagnosed as having the CYP2C9 *2 variant.
In John’s case a genetic variant resulted in a potentially life-threatening adverse event while in Sally’s case a genetic variant resulted in requiring a lower dose of the drug.
Just as one pair of jeans does not fit all so one drug does not fit all and part of the reason is genetic variation.
The idea behind pharmacogenetics — that a person’s genes influence their responses to medicinal drugs — is not new1. The history of pharmacogenetics stretches as far back as 510 b.c. when Pythagoras noted that ingestion of fava beans resulted in a potentially fatal reaction in some, but not all, individuals2.
Pharmacogenetic variation (eg. in acetylation, hydrolysis, oxidation, or drug-metabolizing enzymes) can have clinical consequences. For example, if patients metabolize certain drugs rapidly, they may require higher, more frequent doses to achieve therapeutic concentrations; if patients metabolize certain drugs slowly, they may need lower, less frequent doses to avoid toxicity, particularly of drugs with a narrow margin of safety3.
In short, some genetic variants make drugs toxic for some; others render certain drugs ineffective1.
Pharmacogenetics has become one of the leading and potentially most actionable areas of personalized medicine, as evidenced by the increased availability of clinical pharmacogenetic testing among CLIA-approved laboratories over the past few years4. Currently, variations in around 20 genes provide useful predictions of reactions to 80–100 drugs — about 7% of drugs approved by the US Food and Drug Administration1,3.
Guidelines have been developed by the NIH-funded Clinical Pharmacogenetics Implementation Consortium (CPIC) to assist physicians in dealing with the results. This is an international group of pharmacogenetics experts who have so far produced detailed practical advice on 33 drug–gene pairs5.
In practice, however, only a handful of specific tests are routinely used in the clinic today. An example is the antiretroviral agent abacavir, which is prescribed to people who have HIV. Up to 10% of Caucasians carry a particular version of an immune-system gene called HLA-B that gives them a 50% chance of experiencing a life-threatening hypersensitivity reaction to abacavir. Within a few years of the risk allele being identified in 2002, clinics started screening for it before commencing antiretroviral therapy, offering alternative medicines to those with the problematic variant. This decreased the incidence of hypersensitivity, and HLA-B screening is now standard care for HIV patients1.
In an effort to enable further evidence of clinical utility in the post-market period, the FDA Amendments Act of 2007 allows for systematic, ongoing efforts to continue developing evidence for safety and effectiveness after drug approval. Drug product labeling has also been revised after approval to include pharmacogenetic information that can alter the benefit/risk relationship, or allow dosing of the medicine to be adjusted for individuals6.
It is hoped that full ascertainment of genomic information on all subjects during early development will allow early discovery of clinically important genomic differences. As a result, the Food and Drug Administration (FDA) released a “Guidance for Industry Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical Studies.” The purpose of the guidance is to suggest approaches to improve the quality of the data collected and the ability to assess genomic relationships. The guidance is also intended to assist the pharmaceutical industry and other investigators engaged in new drug development in evaluating how variations in the human genome could affect the clinical pharmacology and clinical responses of drugs. The guidance provides recommendations on when genomic information should be considered to address questions arising during drug development, and in some cases, during regulatory review6,7. Also, ICH E15 provides an agreement on definitions to facilitate the integration of pharmacogenetics into the global drug development and approval process8.
So please remember the genes early on in your drug development program.
- Pharmacogenetics: The right drug for you. Nature 537, S60-62. 2016
- Pharmacogenetics and pharmacogenomics. Br J Clin Pharmacol. 52 (4):345-347. 2001
- Personalizing medicine with clinical pharmacogenetics. Genet Med. 13(12): 987–995. 2011
- Guidance for Industry Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM337169.pdf
- Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample coding catgegories. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E15/Step4/E15_Guideline.pdf