Pharmacogenetics Testing

Adverse Drug Reactions

  • Adverse Drug Reaction - Term used to describe harm associated with the use of a given medication at a normal dosage during normal use.

  • 5.3% of all hospital admissions are associated with ADRs, and 10.7% for patients over the age of 65 (5).

  • ADRs cause one out of every five injuries or deaths/year to hospitalized patients (5).

  • These adverse reactions cause unnecessary hospitalization, longer hospital visits, and increase healthcare costs by approximately $136 billion annually! (6)

  • This is greater than the total cost of cardiovascular and diabetic healthcare combined!

Preventable Adverse Drug Reactions: A Focus on Drug Interactions [Internet]: FDA; c2016 [cited 2016 10/10]. Available from: http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm110632.htm#ADRs: Prevalence and Incidence.

Current Standard Operating Procedure For Clinical Care: Same Diagnosis, Same Prescription

Factors That Affect Drug Metabolism

• Age

• Gender

• BMI

• Comorbidities (e.g. liver or renal dysfunction)

• Concomitant medications

• Genetics

Pro Drugs and Active Drugs

Pharmacokinetics

•What the body does to the drug.

•Metabolism, bioavailability.

•Pro-drugs and active drugs.

•Washing the active agent from the body.

Pharmacodynamics

•What the drug does to the body.

•Therapeutic results?

•Sub-therapeutic results?

•Toxic results?

Chemistry Connections [Internet]: Agent of Chemistry; c2016 [cited 2016 10/10]. Available from: http://agentofchemistry-rogertam.weebly.com/chemistry-connections.html.

Medications typically fall into one of two categories: pro drugs and active drugs. When an active drug is ingested it is absorbed into the bloodstream and transported to it's primary target site within the body where it is metabolized and/or recieved in order to produce a theraputic effect. When a pro drug is ingested it is absorbed into the bloodstream and transported to it's primary target site within the body (typically the liver). This primary target site is where the pro drug is then metabolized into its active form. This newly activated metabolite then leaves the liver and is transported to its secondary target site in the body where it is further metabolized and/or recieved in order to produce a theraputic effect (1).

Genetics & Drug Metabolism

The cellular machinery responsible for metabolizing pro drugs into their active forms are tiny functional proteins called "Enzymes". The cellular machinery responsible for receiving active drug molecules are tiny functional membrane-bound proteins called "Receptors". Specific enzymes metabolize select corresponding medications and specific receptors interact with select corresponding active drug molecules. These highly specific proteins are produced from corresponding segments of DNA known as "Genes". Humans possess an estimated 20,000 - 25,000 protein-coding genes!

 

A gene is essentially a blueprint for a specific protein. Humans inherit two copies of each gene, one from each parent. These gene copies are known as "Alleles", and within a population there is often many different versions of alleles for each gene. Inheriting two alleles per gene is advantageous because it serves as a mechanism of redundancy and also results in increased genetic variation. The combination of an individual's maternal and paternal alleles make up that person's "Genotype" for that gene. That genotype will then manifest into a particular "Trait" that the individual possesses. A similar term, "Phenotype" is used to describe a trait that corresponds with a specific genotype. Using eye color as an example, common phenotypes would include blue eyes, green eyes, and brown eyes (each is the result of a different genotype).

 
 
 

The Cytochrome P450 Family of Enzymes

Cytochrome (CYP) P450 is a family of enzymes that are responsible for the biotransformation of over 90% of commonly prescribed medications! These enzymes are highly concentrated in the liver and are intimately involved in metabolizing pro drugs into active drug metabolites (2,3). 

Cytochrome P450 Phenotype Variation

Lynch, Price. The Effects of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects. Eastern Virginia Medical School: ; 2007.

Traditional CYP450 Phenotypes

  • Ultra Rapid Metabolizer - Variant alleles and/or an increased number of gene copies may be present. Drug is metabolized too quickly, may need lower/higher dose or a different drug depending on the medication (pro-drug vs active drug).

  • Normal Metabolizer (aka extensive or rapid metabolizer) - No variant alleles present, responds well to standard medication and dose.

  • Intermediate Metabolizer - One variant allele present, may need lower dose or different drug depending on the medication.

  • Poor Metabolizer - Two variant alleles and/or a decreased number of gene copies may be present. Drug is metabolized or eliminated too slowly. Higher levels remain in the patient’s system, may need decreased dosage or a different drug depending on the medication (2).

CYP3A5 Phenotypes

  • Nonexpresser - Two variant alleles (in the promoter regions of both the maternal and paternal gene copies). This results in a lack of sufficient gene expression, the first step in enzyme production. 72.3% of the population are CYP3A5 nonexpressers, and they typically dictate "standard dosing" guidelines for CYP3A5 metabolized medications.

  • Intermediate expresser - One variant allele present (in the promoter region of either the maternal or paternal gene copy) resulting in a higher amount of gene expression. Higher dose or different drug may be recommended depending on the medication.

  • Expresser -  No variant alleles present (in the promoter region of both the maternal and paternal gene copies) resulting in the highest amount of gene expression. A higher dose or different drug may be recommended depending on the medication (2).

CYP450 Enzyme Phenotype Prevalence

Hocum BT, White Jr. JR, Heck JW, Thirumaran RK, Moyer N, Newman R, Ashcraft K. Cytochrome P-450 gene and drug interaction analysis in patients referred for pharmacogenetic testing. American Journal of Health-System Pharmacy 2016 01/15;73(2):61-7.

Risk Phenotype Prevalence and Distribution In Patients Who Underwent Testing Focused On All Five CYP Isozyme–Encoding Genes (n = 22,000+)

Hocum BT, White Jr. JR, Heck JW, Thirumaran RK, Moyer N, Newman R, Ashcraft K. Cytochrome P-450 gene and drug interaction analysis in patients referred for pharmacogenetic testing. American Journal of Health-System Pharmacy 2016 01/15;73(2):61-7.

The figure above shows the percentage of the 22,000+ patients tested that possessed variant phenotypes with respect to the following five genes: CYP2C19, CYP2D6, CYP3A4, CYP3A5, and CYP2C9. 14,578 of these patients possessed multiple CYP450 variant phenotypes! Seven percent of patients had no variant CYP450 genes. Thirty-three percent of patients had one variant CYP450 gene. Forty-one percent of patients had two variant CYP450 genes. Seventeen percent of patients had three variant CYP450 genes. Only two percent of patients had four variant CYP450 genes, and none of the patients tested possessed variant phenotypes for all five CYP450 genes (2). 

Summary

  • There is a wide range of variability in patient response to commonly prescribed medications.

  • Genetics is estimated to account for up to 90% of the variability in drug response (3).

  • Pharmacogenomic testing provides a genetic “scouting report” on each individual and helps doctors prescribe an optimal medication and dosage selection for each patient, the first time, every time!

  • This test is performed using a non-invasive buccal (cheek) swab!

  • Pharmacogenomics can eliminate the trial and error approach associated with many prescription medications!

  • This type of testing can save nearly 100,000 lives and over $136 billion dollars annually! (5,6)

References

 1) Chemistry Connections [Internet]: Agent of Chemistry; c2016 [cited 2016 10/10]. Available from: http://agentofchemistry-rogertam.weebly.com/chemistry-connections.html.

2) Hocum BT, White Jr. JR, Heck JW, Thirumaran RK, Moyer N, Newman R, Ashcraft K. Cytochrome P-450 gene and drug interaction analysis in patients referred for pharmacogenetic testing. American Journal of Health-System Pharmacy 2016 01/15;73(2):61-7.

3) Lynch, Price. The Effects of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects. Eastern Virginia Medical School: ; 2007.

4) Menu of Tests [Internet]Louisville, KY: PGXL Laboratories; c2016 [cited 2016 11/20]. Available from: http://www.pgxlab.com/test-menu/.

5) Preventable Adverse Drug Reactions: A Focus on Drug Interactions [Internet]: FDA; c2016 [cited 2016 10/10]. Available from:http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm110632.htm#ADRs:PrevalenceandIncidence.

6) Systemic Review on Drug Related Hospital Admissions – A pubmed based search. Nivya et al. 2015.

7) Translational Bioinformatics -PLOS Computational Biology. Lewitter et al. 2012. 

 
 
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