Britt Franken reveals how personalised medicine is aiding physicians in selecting the best therapeutic strategy
Physicians have long been aware of the subtle differences between patients in their responses to medications. The recognition that a part of this variation is inherited, and therefore predictable, created the field of pharmacogenetics several years ago.
Pharmacogenetics studies the influence of genetic variation on drug response. Knowledge of gene variants causing differences in drug response among patients has the potential to allow ‘personalised’ drug therapy.
A patient’s response to a drug is often linked to common genetic variations present in their genes. One type of genetic variation is single nucleotide polymorphisms (SNPs). Knowing the types of SNPs/genetic variations present in a patient can help predict the associated drug response. This may not only help physicians individualise drug therapy, it can also help improve effectiveness of the drug, decrease the chance of negative side effects and save healthcare costs.
An accurate prediction about drug response is crucial for individualised treatment. This is best made by combining an individual’s genetic data with clinical findings and classifying individuals into subpopulations that differ in their response to a specific drug. Using this approach, healthcare providers may be better equipped to move beyond the ‘one size fits all’ treatment strategy that defined much of patient care in the past, to care that is appropriate for specific patient subgroups.
The discovery of genetic factors such as the cytochrome P450 (CYP) drug metabolising genes and several years of subsequent clinical research have added to our understanding of the clinically relevant genetic variations that may help predict drug response.
Genetic variation and drug efficacy
The extents to which patients metabolise drugs have significant impact on the effectiveness of their pharmacologic therapy. For example, individuals with genetic variation that results in ultra-high metabolism of drugs can experience therapeutic failure on the standard dose of a drug, due to rapid clearance of the drug from their system.
To a large extent, the CYP450 genotype of a patient determines the level of enzyme activity (‘phenotype’), which can be classified into four groups:
* Extensive metabolisers (EMs) have normal enzymatic activity, and carry either two wild-type alleles, or one wild-type allele and one decreased activity or null allele.
* Intermediate metabolisers (IMs) have decreased enzymatic activity, and carry either two decreased activity alleles, or one decreased activity allele and one null allele.
* Poor metabolisers (PMs) have absent enzymatic activity, and carry two null alleles.
* Ultra-rapid metabolisers (UMs) have increased enzyme activity, and have gene duplications or multiplications of the CYP2D6 gene (more than two copies of the gene).
Typical drug efficacy rates range from 25-80%, with most drugs falling in the range of 50-60%.
Genetic variation and adverse drug reactions
Adverse drug reactions (ADR) due to variability in drug responses are often preventable and remain an underappreciated clinical issue. The Food & Drug Association Adverse Events Reporting System (FAERS) estimated 800,000 ADRs in the USA and Europe combined for the year 2011.1 The incidence of serious and fatal ADRs has been rising with the increase in the number of medications prescribed. An estimated US$3.5bn is spent on additional medical costs associated with ADRs annually and at least 40% of this may be preventable.2
Drugs may be metabolised by more than one pathway involving several enzymes of the cytochrome P450 class. Cytochrome P450 enzyme 2D6 (CYP2D6) alone is thought to be active in the enzymatic breakdown of 20-25% of all medicines prescribed,2 including antidepressants, antipsychotics, opioids, beta-blockers, antiarrhythmics and tamoxifen.
Cytochrome P450 enzyme 2C19 (CYP2C19) metabolises many clinically important drugs including proton pump inhibitors, antidepressants, the antiplatelet drug clopidogrel, and the antifungal voriconazole.3
Laboratory techniques to detect drug response variability exist currently. Phenotyping and/or genotyping are the primary methods. Phenotyping is done by measuring enzyme activity directly using a probe drug whose metabolism is known to be solely dependent on the particular CYP enzyme. However, using a probe drug to measure individual phenotypes has limitations.
Drugs, diet or environmental factors do not affect genotyping results. Genotyping assays by molecular methods are fast, reliable and accurate, and are not affected by drugs, diet or environmental factors. The interpretation of the genotype result to the phenotype is based mainly on literature, and on the physician’s judgment.
Identification of patient genotypes for clinically relevant CYP genes can help physicians tailor drug treatment to patients.These measures may improve a physician’s ability to impact patient outcome by ensuring maximum drug efficacy with minimal adverse drug reactions.4
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Pierre van Aarle is with Luminex in the Netherlands.
References: 1 FDA. FAERS Domestic and Foreign Reports by Year. 2012 June 30, 2012. Cited 2013. Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm070441.htm; 2 CDC. Medication Safety Basics. Cited 2013.Available from: http://www.cdc.gov/medicationsafety/basics.html; 3 Samer CF, et al. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther 2013; 17(3):165-184; 4 FDA. Drug interactions and Labelling. 2009. Cited 2013. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/default.htm.