DRUG DISCOVERY & DEVELOPMENT 41
Illustrating the concepts of medicine today versus the personalised medicine that we are heading towards.
l Intermediate metabolisers (IMs) have decreased enzymatic activity, and carry either two decreased activity alleles, or one decreased activity allele and one
null allele. l Poor metabolisers (PMs) have absent enzymatic activity, and
carry two null alleles. l 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. Te Food & Drug Association Adverse Events Reporting System (FAERS)
FDA. FAERS Domestic and Foreign Reports by Year. 2012 June 30, 2012. Cited 2013. Available from:
http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Surveillance/
REFERENCES 1
AdverseDrugEffects/
ucm070441.htm. 2
www.cdc.gov/medicationsafety/basics.html. 3
setting. Mol Diagn Ther 2013; 17(3):165-184. 4
CDC. Medication Safety Basics. Cited 2013.Available from: http:// Samer CF, et al. Applications of CYP450 testing in the clinical FDA. Drug interactions and Labelling. 2009. Cited 2013. Available
from:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/DrugInteractionsLabeling/
default.htm.
estimated 800,000 ADRs in the USA and Europe combined for the year 2011.1
Te 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
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.
including
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. Te 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. Tese measures may improve a physician’s ability to impact patient outcome by ensuring maximum drug efficacy with minimal adverse drug reactions.4
For more information ✔ at
www.scientistlive.com/eurolab
Pierre van Aarle is with Luminex in the Netherlands.
www.luminexcorp.com/ pharmacogenetics
www.scientistlive.com
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