Pharmacogenomics

Published on 16/06/2015 by admin

Filed under Basic Science

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 2 (3 votes)

This article have been viewed 1921 times

CHAPTER 29 Pharmacogenomics

I. Introduction

A. Pharmacogenomics is the study of how interindividual genetic variations affect the response to drug therapy, including the influence of these variations on drug disposition (pharmacokinetics) and desirable or undesirable drug effects (pharmacodynamics). The term pharmacogenetics is closely related to pharmacogenomics, and the terms are often used interchangeably.1
B. There are small variations in genetic sequencing among humans. Genetic polymorphisms are DNA sequencing variations that occur with at least a frequency of 1% in the population; polymorphisms are responsible for significant alterations in the way a given person responds to a given drug. The effects may be pharmacokinetic or pharmacodynamic in nature; examples are given in the following review.

1. Pharmacokinetic effects: Several genetic polymorphisms affecting drug metabolism via changes in enzymatic activity or transport proteins have been identified. Well-known examples include genetically-induced alterations in the activity of cytochrome P-450 (CYP) 2D6, CYP 2C19, and thiopurine methyltransferase. Many common drugs are affected by such alterations, including warfarin, codeine, antiarrhythmic agents, antidepressants, phenothiazine antipsychotics, and thiopurines such as mercaptopurine and azathioprine.
2. Pharmacodynamic effects: Identifying expression of certain genetic traits within the context of a disease may result in more specifically targeted drug therapy with improved response rates and lowered risk for toxicity. Targets are often cellular receptors or signal transduction modulators. A well-known example is the development of the drug trastuzumab (Herceptin) and its activity in cancers (particularly breast cancer) where the over-expression of the ERBB2 (HER2/neu) oncogene is present in the tumor. Other examples include the recent findings that certain human leukocyte antigen (HLA) expressions predispose some patients to serious hypersensitivity reactions of specific medications. HLA proteins play a role in recognizing foreign substances in the body and in the subsequent immune responses. Examples of drugs where HLA subtype expression plays a role in hypersensitivity include abacavir, allopurinol, carbamazepine, and phenytoin. Testing individuals for the expression of these HLA subtypes before selecting drug therapies may prevent serious adverse consequences in susceptible individuals. Certainly, genetic differences may also account for the presence of certain traits or diseases that may affect pharmacodynamic responses to drugs. Examples include Factor V Leiden mutations, which may predispose female patients with the mutation to be at risk of thromboembolism while taking oral contraceptives.

II. Benefits of Identifying Pharmacogenomic Variables

The field of pharmacogenomics is in its infancy. However, important and tangible recommendations for personalized prescribing are beginning to emerge. Pharmacogenomic variables are now identified for a few commonly prescribed drugs. Recommendations regarding laboratory testing and prescriber actions are now incorporated into the official prescribing literature for these drugs (Table 29-1). For other drugs, recommendations are not yet defined (Table 29-2). Pharmacogenomics is a rapidly changing discipline, and many factors, including health care costs, patient preferences, and the overall health of the patient will ultimately influence the individualization of any therapy.1

A. Benefits that can be derived via better understanding of pharmacogenomics:

1. Identify populations at risk for significant allergy or toxicity; avoid risky medications in populations in which risk outweighs benefit
2. Potential for greater overall safety in the use or dosing of a particular drug, allowing drugs to remain marketed rather than pulled from market for safety
3. Ability to individualize drug therapy, increasing disease response rates via appropriate drug selection

III. Testing for Pharmacogenomic Data

A. There are two categories of pharmacogenomic tests.

1. FDA approved (not common)
2. Clinical Laboratory Improvement Ammendments (CLIA)–compliant: independent laboratory test regulation program to ensure quality of testing

B. As of early 2009, the following pharmacogenomic tests were FDA approved

1. Amplichip (tests for CYP 2D6, CYP 2C19)
2. Invader Assay (tests for UGT1A1)

C. FDA approval of other tests is currently pending. Several tests can also be ordered from independent CLIA-compliant laboratories. There is a searchable database for these laboratory tests at http://www.fda.gov/cdrh/clia.

IV. Conclusion

TABLE 29-1 Example Drugs With Known Pharmacogenomic Variables and Well Defined Recommendations in U.S. Product Labeling

image image

Table 29-2 Other Drugs with Pharmacogenomic Variables*

Drug/Drug Class Biomarker Potential Clinical Effect
Antidepressants
Antipsychotics
Antiarrhythmics
Beta blockers

CYP 2D6
For selected drugs in classes only
Greater likelihood of ADR or need for dose reduction in poor metabolizers; possible treatment failures in rapid metabolizers
5-Fluorouracil or capecitabine Dihydropyridine dehydrogenase (DPD)
Rare, unexpected, and severe toxicity (e.g., stomatitis, diarrhea, neutropenia, and neurotoxicity) attributed to deficiency of DPD activity
Results in prolonged clearance of these chemotherapies
Other chemotherapy agents Various (e.g., tyrosine kinase, CYP variants)
Targeting of cells with various markers results in increased chemotherapy efficacy
Poor metabolizers may have risk for drug toxicity
General anesthetics Ryanodine receptor (RYR1) Increased risk of malignant hyperthermia if biomarker is present Oral contraceptives (OC) or tamoxifen Factor V Leiden mutations May increase risk for deep vein thrombosis or other blood clots Proton pump inhibitors (PPI) CYP 2C19 Rapid metabolizers may experience treatment failures

* Defined action may be available in future, currently prescriber actions not well defined.

Pharmacists and other health care providers are encouraged to familiarize themselves with current guidance and rapid changes occurring in the field of pharmacogenomics. Current guidance has resulted in strong recommendations for screening before initiation of drug therapy or for the adjustment of drug dosages during therapy for selected drugs. Continuing education programs are available through organizations such as the American Medical Association and Food and Drug Administration.13

References

1. U.S. Department of Health and Human Services. Report of the Secretary’s Advisory Committee on Genetics, Health, and Society. Realizing the potential of pharmacogenomics: opportunities and challenges. May 2008 http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS_PGx_report.pdf Accessed March 2009

2. Phillips E.J. Genetic screening to prevent abacavir hypersensitivity reaction: are we there yet? Clin Infect Dis. 2006;43:103-105.

3. Ziagen, Epzicom. Trizivir package inserts: Research Triangle Park. NC: GlaxoSmithKline, 2009.

4. Strattera package insert, 2008 Indianapolis:Eli Lilly and Company

5. Imuran package insert, 2008 San Diego:Prometheus Laboratories

6. Tegretol package insert, 2008 East Hanover:Novartis

7. Tylenol with codeine package insert, 2007 Raritan:Ortho-McNeil Pharmaceuticals

8. Camptosar package insert, 2008 New York:Pfizer

9. Purinethol package insert, 2007 Sellersville:Gate Pharmaceuticals

10. Tabloid package insert, 2004 Research Triangle Park:GlaxoSmithKline

11. Herceptin package insert, 2008 San Francisco:Genentech, Inc

12. Coumadin package insert, 2007 Princeton:Bristol-Myers Squibb Co

13. The American Medical Association and the Food and Drug Administration (FDA). Pharmacogenomics and Personalized Medicine. June 2007 Web-based training ama.learn.com/login Accessed March 2009

REVIEW QUESTIONS

(Answers and Rationales on page 384.)

1. Which of the following statements about codeine would indicate that a patient is a poor metabolizer of CYP 2D6?

a. “I took codeine once after surgery. It worked very well and fast, but I got dizzy and pretty sleepy.”
b. “I took codeine once after surgery, and to be honest, it did not seem to do that much for me. They switched my medication to morphine and that was much better.”
c. “Codeine worked for me just fine, and I did not have any side effects.”

2. Which of the following best describes the proper use of trastuzumab for breast cancer?

a. In patients with positive estrogen receptors
b. In patients who overexpress the ERBB2 (HER2/neu) oncogene
c. To target a tumor necrosis factor (TNF) within the tumor

3. A young male patient with newly diagnosed HIV infection is being considered for treatment with an abacavir-containing regimen to increase compliance. His genetic testing comes back positive for the HLA-B*5701 allele. What is the best course of action for this patient?

a. Initiate abacavir at a low dosage and monitor for side effects
b. Choose an alternative to abacavir for this patient
c. Continue with abacavir regimen as planned

4. A lower starting dosage is recommended for patients who take warfarin and have reduced activity of:

I. CYP 2C9
II. CYP 3A4
III. CYP 2D6
IV. VKORC1
a. Both I and IV
b. II only
c. Both II and III
d. IV only

Related posts:

Default ThumbnailDrug Information Resources Default ThumbnailPain Management Default ThumbnailWomen’s Health Issues Immunology and Vaccines Pharmaceutical Calculations Respiratory Disorders