Lean about the revolutionary process that’s changing prescribing.
The role of genetics in drug metabolism
It is now clear that virtually every pathway of drug metabolism, transport, and action is susceptible to genetic variation. It is estimated that 20-90% of an individual's variation to drug response is based on genetics.i Within the top 200 selling prescription drugs, 59% of the 27 most frequently cited in adverse drug reaction (ADR) studies are metabolized by at least one enzyme known to have gene variants that code for reduced-functioning or non-functioning proteins. This compares with 7% of a random selection from the top 200 list.ii Many other factors such as age, physiological functioning, and concomitant disease are known and can be accounted for, leaving the genotype of the patient as a major unknown factor in the prescribing of medicines.
ADRs: A serious medical problem
In 2000, Genelex began offering physicians an alternative to the “one size fits all” and “trial and error” prescribing of drugs. All too often, a serious adverse drug reaction (ADR) is the result. ADRs are not medical errors, but events that occur in spite of compliance with dosage recommendations. A 1998 meta-analysis of 39 prospective studies in US hospitals estimated that 106,000 Americans die annually from ADRs.iii Adverse drug events are also common (50.1 per 1,000 person-years) among ambulatory patients, particularly the elderly on multiple medications. The 38% of events classified as serious are also the most preventable.iv
Pharmacogenetic testing is the alternative to “one size fits all” and “trial and error” prescribing. Knowledge of patient drug metabolizing gene variants—found in more than half of patients—can help determine the appropriateness and dosage of many of the most commonly prescribed drugs, including:
- SSRI and TCA antidepressants
- opioid pain medications
- beta blockers
- Type I antiarrhythmics
Genelex currently offers genetic tests that reliably identify and classify CYP2D6, CYP2C9 (with VKORC1 for warfarin), CYP2C19, CYP3A4, CYP3A5, CYP1A2, and NAT2 into their slow, normal, and ultra-fast metabolizing forms.
Individualized patient reports based on patient drug, herbal, and diet regimens
YouScript reports include patient-specific information on potential drug-to-drug interactions (DDIs) mediated by the tested polymorphic drug metabolizing enzymes, taking into account patient diet and OTC and herbal medicines. YouScript provides physicians with immediate insight into individual differences in their patients' drug processing ability and helps physicians improve the efficacy and safety of the prescribed treatments. This information can be especially valuable when potential DDIs are a possibility.
DNA testing and personalized medicine
YouScript provides information on the highly polymorphic cytochromes CYP2D6, CYP2C9 (includes VKORC1), CYP2C19, CYP3A4 and CYP3A5. These enzymes process 40% of commonly prescribed drugs processed by the liver, including many with narrow therapeutic indices and frequent participation in drug-to-drug interactions.v About 85% of the population have genetic variations that can lead to altered or absent gene function, resulting in elevated patient susceptibility to adverse drug reactions. Genotyping to avoid ADRs is a dependable tool to improve your practice today and begins your transition to the practice of tomorrow.
- Maximizes treatment success by individualizing patient treatments to match their unique genetic make-up
- An opportunity to build your practice
- Minimizes liability by reducing “trial and error” prescribing
- Keeps your practice current with the latest advances in genetic science
- Provides personalized and clinically-relevant drug-to-drug and/or drug-to-gene interaction information
- Helps the patient’s physician optimize the safety and efficacy of prescription regimens
- Proactive treatment choices
Pharmacogenetic effect of cytochrome genotypes
A. PM, Poor Metabolizer: absent or greatly reduced ability to clear or activate drugs.
B. IM, Intermediate Metabolizer: heterozygotes for normal and reduced activity genes.
C. EM, Normal Metabolizer: the norm.
D. UM, Ultra Rapid Metabolizer: greatly increased activity accelerating clearance or activation
Population frequency of cytochrome P450 (CYP) genotypes
RM & UM
*CYP2C19 variability depends on ethnicity
Currently available tests
Included as part of YouScript
CYP2D6 (cytochrome P450 2D6, includes VKORC1) is the best studied of the DMEs and acts on one-fourth of all prescription drugs metabolized by the liver, including the selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), beta blockers such as Inderal and the Type 1A antiarrhythmics. Approximately 10% of the population has a slow acting form of this enzyme and 7% a super-fast acting form. Thirty-five percent are carriers of a non-functional 2D6 allele, especially elevating the risk of ADRs when these individuals are taking multiple drugs. Drugs that CYP2D6 metabolizes include Prozac, Zoloft, Paxil, Wellbutrin, hydrocodone, amitriptyline, Haldol, metoprolol, Rythmol, tamoxifen, and the over-the-counter diphenhydramine drugs, Allegra, Dytuss, and Tusstat. CYP2D6 is responsible for activating the pro-drug codeine into its active form and the drug is therefore inactive in CYP2D6 slow metabolizers.
CYP2C9 (cytochrome P450 2C9) is the primary route of metabolism for Coumadin (warfarin) and Dilantin (phenytoin). Approximately 10% of the population are carriers of at least one allele for the slow-metabolizing form of CYP2C9 and may be treatable with 50% of the dose at which normal metabolizers are treated. Other drugs metabolized by CYP2C9 include Amaryl, isoniazid, sulfa, ibuprofen, amitriptyline, Hyzaar, THC (tetrahydrocannabinol), naproxen, and Viagra.
CYP2C19 (cytochrome P450 2C19) is associated with the metabolism of Plavix, carisoprodol, diazepam, Dilantin, and Prevacid.
CYP3A4 and CYP3A5 (cytochrome P450 3A4 and 3A5) are two closely related drug-processing enzymes which are responsible for the metabolism of about half of the most commonly prescribed drugs, including medications used to treat heart disease, pain, cancer and infectious disease. Approximately 5-7% of patients of European descent carry at least one slow-acting form of CYP3A4. Prevalence of CYP3A5 variants vary widely by ethnicity. Notable drugs metabolized include cyclosporine, tacrolimus, simvastatin, and oxycodone.
CYP1A2 (cytochrome P450 1A2) is associated with the metabolism of amitriptyline, olanzapine, haloperidol, duloxetine, propranolol, theophylline, caffeine, diazepam, chlordiazepoxide, estrogens, tamoxifen, and cyclobenzaprine.
NAT2 (N-acetyltransferase 2) is a second-step DME that acts on isoniazid, procainamide, and Azulfidine. The frequency of the NAT2 “slow acetylator” in various worldwide populations ranges from 10% to more than 90%.
5HTT for SSRIs. About 40% of the North American population has a genetic variation in the promoter region of the Serotonin Transporter (5HTT) gene associated with having reduced efficacy towards serotonin-selective reuptake inhibitors (SSRIs) and may respond slower or require therapy from a different class of medications in populations of European ancestry.
UGT1A1 (UDP-glucuronosyltransferase) for Camptosar (irinotecan). The active form of irinotecan, SN-38, is metabolized by UGT1A1 (UDP-glucoronosyltransferase), which is highly polymorphic. An estimated 10% of patients have a genetic variation in UGT1A1*28 that increases the risk of severe, or even fatal, neutropenia at standard dosing levels.
DPD (Dihydropyrimidine Dehydrogenase) for Fluorouracil (5-FU). 5-FU (fluorouracil) is metabolized by dihydropyrimidine dehydrogenase (DPD), which is highly polymorphic. An estimated 3-6% of patients have a genetic variation in DPD that can result in severe toxic reactions that may be fatal with even small doses and often the very first dose of 5-FU.
HLA-B*5701 for abacavir. Tests for sensitivity to Ziagen, a medication prescribed to treat HIV, as well as combination drugs containing abacavir, namely Trizivir and Epzicom - about 8% of those who take the drug will have a hypersensitivity reaction that can be life-threatening.
i. Kang J. Testing Pathway-Dose Interaction in Clinical Studies. 2013 Joint Statistical Meeting - American Statistical Association. 2013 Aug. Available from: http://www.amstat.org/meetings/jsm/2013/onlineprogram/AbstractDetails.cfm?abstractid=309704.
ii. 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(18):2270-2279.
iii. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998 Apr;279(15):1200-5.
iv. Gurwitz JH, Field TS, Harrold LR, Rothschild J, Debellis K, Seger AC et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003 Mar;289(9):1107-16.
v. Cozza KL, Armstrong SC, Oesterheld JR. Concise Guide to Drug Interaction Principles for Medical Practice. 2nd ed. American Psychiatric Publishing; 2003.