Individual patient response to medications is influenced by genetic variation in the enzymes responsible for drug metabolism as well as targeted receptors and transporters. The family of cytochrome P450 genes code for enzymes responsible for approximately 80% of phase 1 drug metabolism. Genetic variation of these genes alone is estimated to influence 20-25% of all drug therapies to the extent that outcome is affected.1
Variations in metabolism can cause life-threatening toxicity in one patient and reduce drug effectiveness in another.2
Clinically significant genetic alterations in the cytochrome P450 (CYP) genes can result in decreased or increased enzyme activity. These alterations in enzyme function are categorized into four phenotypes. Knowing a patient’s metabolic phenotype and its impact on drug metabolism can empower clinical treatment decisions, increase drug efficacy and reduce the risk of adverse events.
Extensive Metabolizers (EM) carry 2 functional genes and have normal enzyme activity. Standard medication dosing is appropriate for extensive metabolizers.
Poor Metabolizers (PM) have severely reduced or no functional capacity to metabolize substrate medications. Poor metabolizers are at risk for side effects due to toxic drug accumulation and may require lower doses.
Intermediate Metabolizers (IM) also have a severely reduced capacity to metabolize drugs and therefore may also require modified drug doses.
In contrast, Ultra-Rapid Metabolizers (UM) typically carry multiple copies of the same gene and have elevated enzyme activity and may need increased drug dosing or decreased drug dosing, in the case of pro-drugs, in order to offset the higher rate of metabolism.
Following determination of a patient’s genetic results, the IDgenetix proprietary algorithm assesses all commonly prescribed medications for both genetic interactions as well as metabolic interactions related to multiple prescriptions, over the counter drugs, herbal medications and supplements, and diet. Each patient report features an easy to read, color coded chart indicating which medications are considered “Use as Directed” and which are “Use with Caution and/or Increased Monitoring”. Gene specific results and associated metabolic activity information are also provided in a summary chart format.
DEPRESSION AND ANXIETY
Many psychiatric drugs are metabolized by the CYP enzymes, including 2D6, 2C19 and 2C9, which are genes included in our IDgenetix tests. The CYP2D6 enzyme, for example, primarily or substantially metabolizes a number of selective serotonin reuptake inhibitors, or SSRI, serotonin-norepinephrine reuptake inhibitors, or SNRI, and tricyclic antidepressants, which are, according to IMS Health, the three most-commonly prescribed drug classes in psychiatry, as well as antipsychotic drugs. Our neuropsychiatric tests also include variant analysis for informative receptor and transporter genes associated with clinical response to psychiatric drugs and risk of side effects, such as HTR2A and HTR2C, which are important factors for psychiatric drugs.
Twenty-four psychiatry drugs are included on the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling as having PGx information in the drug labeling. For example, fluoxetine (marketed by Eli Lilly & Company under the name Prozac), has an FDA black box warning and additional label information for poor CYP2D6 metabolizers.
For additional Information:
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants.
FDA Table of Pharmacogenetic Biomarkers in Drug Labeling
1) Ingelman-Sundberg M, Sim S, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacology & Therapeutics. 2007;116: 496–526.
2) Ingelman-Sundberg M, Rodriguez-Antona C. Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy. Philos Trans R Soc Lond B Biol Sci. 2005;360:1563-1570.
3) Fanikos J, Grasso-Correnti N, Shah R, Kucher N, Goldhaber SZ. Major bleeding complications in a specialized anticoagulation service. Am J Cardiol. 2005;Aug 15;96(4):595-598.
4) Machado M, Iskedjian M, Ruiz I, Einarson TR. Remission, dropouts, and adverse drug reaction rates in major depressive disorder: a meta-analysis of head-to-head trials. Curr Med Res Opin. 2006;Sept. 22(9), 1825-1837.