Not everyone benefits from drug therapy for common medical conditions. Up to 75% of patients may simply not respond to some drugs. Hundreds of thousands of hospitalizations and emergency room visits occur as a result of toxicity. These two extreme outcomes can now be anticipated and prevented through pharmacogenomics which allows individualization of therapy.
Individual genetic differences affect drug response. There is much individual patient difference among the cytochrome P450 drug-metabolizing enzyme family. Pharmacogenomic testing can identify which patients may metabolize certain drugs faster or slower than expected. Over 150
FDA-approved drugs across multiple therapeutic areas have biomarker information in their labeling, encouraging individualization of dosing.
Normal variation in human DNA due to substitution of single nucleotide polymorphisms (SNPs) — a variation in one base of DNA — occur at over
10 million sites within human chromosomes. Many of these result in a
non-functional enzyme or potentially one that has increased activity. Many of these SNPs and altered metabolic enzymatic function are directly tied to various changes in the effects of medications and may even be used to predict clinical response.1
While there are over 30 families of drug-metabolizing enzymes, the hepatic cytochrome P450 (CYP) family is the most important.
The human genome includes 57 CYP genes, classified into 18 families and 44 subfamilies. The CYP 1 to 3 families are the most clinically relevant.2 This relatively small group is responsible for the observed metabolism of over 90% of all marketed drugs, with CYP3A4/5, CYP2D6, CYP2C9, CYP2C19, and CYP1A2 performing most of the reactions.3,4 CYP3A4 and CYP3A5 metabolize 50% of commonly prescribed medications, while CYP2D6 alone is responsible for the metabolism of up to 50% of the remainder. CYP2D6 is encoded by a highly variable gene with over 130 genetic drug-modifying variations.5
Depending on the variations present in a CYP gene, an individual can be classified into one of four phenotypes with respect to the activity of the encoded enzyme. Those who are homozygous normal — typically the majority of the population — inherit two normally functioning alleles and are considered “extensive” metabolizers for that specific enzyme. Intermediate metabolizers (IM) inherit a heterozygous genotype — one functional and one deficient allele — or two partially deficient alleles that result in reduced activity. Individuals who lack a functional enzyme because they have inherited two non-functional alleles and are functionally poor metabolizers (PM). Those who have two or more alleles with extremely high metabolic capacity are considered to be ultra-rapid metabolizers (UM).
Determining how patients metabolize drugs can guide the selection of a drug and dose and help avoid adverse drug reactions. Many drugs are effective in as few as 25% of people. Genetics is the most important factor in determining individual benefit from drugs and can guide optimal dosing.
The FDA requires drug manufactures to include information about a drug’s effects on the cytochrome P450 enzyme family. Active drugs and prodrugs are metabolized in the opposite way, and correctly identifying a patient’s status can make the difference between the desired effect, no effect or even life-threatening toxicity.
A New Approach To Drug-Based Patient Management
The Cytochrome P450
Are Critical For
Fills Emergency Rooms
Variability in drug response is a major clinical problem. Most medications are metabolized by CYP enzymes that are naturally highly variable in activity.1 Adverse drug reactions and therapeutic failures may result.
The Centers for Disease Control and Prevention Medication Safety Program estimates that over 80% of American adults take one medication or more with one third taking at least five. In long-term care facilities residents take on average seven to eight different medications per month, with approximately one third taking more than nine.6
Adverse drug events cause an estimated 700,000 emergency room visits and 120,000 hospitalizations, adding $3.5 billion to the costs of care.7 These are related to unintentional drug toxicity, poor compliance, or unintentional drug under-dose related to metabolic effects.8
Drug-drug interactions (DDIs) occur between two or more drugs and can alter the drug levels (pharmacokinetic interactions) or function (pharmacodynamics interactions).9
Pharmacodynamic interactions occur when drugs act on the same or interrelated receptor sites resulting in additive or antagonistic effects. For example, overstimulation of the 5-HT2A receptor through the combination of an antidepressant and an opioid may result in Serotonin Syndrome characterized by unanticipated psychotrophic effects.10
Pharmacokinetic interactions are caused by one drug interfering with the absorption, distribution, metabolism or excretion of another.1 Drug induction or interference with a specific CYP enzyme frequently affects the metabolism of other drugs. Drug-induced CYP450 inhibition may be so strong that a person genotyped as an intermediate metabolizer may react to a drug as might a poor metabolizer. CYP450 induction would have the opposite effect.
Pharmacogenomic Testing Saves Money
Advice from the
Clinical Pharmacogenetic Implementation Consortium
Cost savings can result from pharmacogenomic testing. One study determined whether patient- and clinician-access to genetic information when selecting psychiatric treatment would influence medication adherence and systemic costs. When genetic testing was performed cost savings of approximately $600 per patient occurred when compared to individuals not genetically tested. These savings resulted from increased medication adherence and a fewer hospital visits.11
In another study, Medco Health Solutions patients (n=3,584, average age of 65) starting on warfarin were managed using CYP450 genetic testing and compared to a matched historic group managed conventionally. During the six-months after-treatment initiation, the genotyped cohort had 28% fewer hospitalizations due to bleeding or thromboembolism and had 31% fewer hospitalizations overall.12 The average hospital stay costs $10,000 per day.13 Cost savings, as a result of increased medication adherence, fewer adverse drug reactions, and fewer hospitalizations, can be realized when therapy is individualized to specific genetic results.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) was formed in 2009 to guide clinicians and laboratories in the appropriate use of pharmacogenomic testing. The group comprises Pharmacogenomics Research Network members, and experts in pharmacogenomics, pharmacogenetics and laboratory medicine.14
The CPIC currently provides in-depth recommendations for 28
FDA-approved medications (although over 150 have biomarker information in their labeling). One example is tricyclic antidepressant use:
“There is substantial evidence linking CYP2D6 and CYP2C19 genotypes to phenotypic variability in tricyclic side-effect and pharmacokinetic profiles. Modifying pharmacotherapy for patients who have CYP2D6 or CYP2C19 genomic variants that affect drug efficacy and safety could potentially improve clinical outcomes and reduce the failure rate of initial treatment.”
Additional guidelines can be found at www.PharmGKB.com
Adverse Drug Reactions
The US Food and Drug Administration (FDA) defines a Serious Adverse Drug Reaction (SADR) as any undesirable or unpredicted medication event that results in death, a life-threatening condition, hospitalization, disability, or congenital anomaly, or that requires intervention to prevent one of these outcomes.5 It identifies the risk of such event within the drug monograph as “Black Box Warnings”. The best indicator for individual risk of an SADR for any specific patient may be found within the patients DNA. Around 200 classes of drugs carry Black Box Warnings. In 2010 alone, the FDA’s Adverse Events Reporting System (AERS) logged over 470,000 SADRs, with over 82,000 adverse reactions leading to death.1
Your patients count on you
to help protect them
from these risks.
Genetic Testing and
Black Box Warnings:
What You Need To Know
Genetic testing is advised before prescribing many drugs with Black Box Warnings. For example, in 2010, the FDA announced that patients taking the cardiovascular drug clopidogrel (Plavix), who have a specific variation of the CYP2C19 gene, are less likely to respond to the drug, which may place them at continued risk for heart attack and stroke.2 Genetic analysis of the CYP2C19 gene can determine if a patient is a poor metabolizer. Integrating pharmacogenomics into clinical care can enable the practitioner to individualize treatment and avoid potential life-threatening adverse events.
Pharmacogenomics can direct the use of 150 FDA-approved drugs which have pharmacogenomics guidance within their monograph.
As the utilization of pharmacogenomic testing increases there will be fewer drug reactions, less non-compliance due to side effects and lower healthcare costs.
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