Pharmacogenomics

Individual variation in response to medications is a significant clinical problem. Such variation ranges from failure to respond to a drug, to unwanted adverse drug reactions and drug-drug interactions when several drugs are taken together. 

Inter-individual variability of drug response results from many factors including genetic factors. This genetically determined variability in drug response is the area of medicine called pharmacogenomics. In fact approximately 98% of us have at least one genetic variant in a gene that impacts medication response, while 79% of us have three or more such variants.

More than 98% of us have at least one genetic variant in a gene that impacts medication response, while 79% of us have three or more such variants.

Genetically determined variability in the activity of many drug metabolising enzymes found in the liver has a profound effect on drug efficacy. For example, some people are phenotypically poor metabolisers. Their genetic makeup leads to a complete absence of enzyme activity and a severely compromised ability to metabolise many commonly prescribed drugs.

In these individuals, standard drug doses are not cleared from the body as efficiently as others, hence drug levels are found well above the therapeutic range. As an example, some individuals have a genetic profile that prevents them efficiently clearing a commonly prescribed anticoagulant called warfarin, from the body. Given a standard dose, these individuals are at higher risk of experiencing a serious bleeding event. 

Conversion of a Drug to its Active Form

Genetic differences not only affect drug disposition but can also be important in the conversion of prodrugs to their active form. The analgesic pain medication codeine is metabolised to morphine by the liver enzyme called CYP2D6. In individuals who have the genetic variant of CYP2D6 making them poor metabolisers, are unable to achieve the desired analgesic effect since the efficient conversion of codeine to morphine is not available. In such cases, alternate pain medication is required.

Rapid Enzyme Activity

Some individuals may inherit multiple copies of the drug metabolising gene. This inheritance results in affected people metabolising drugs so quickly that a therapeutic effect cannot be obtained at conventional doses. For example, while a low daily dose of the antidepressant, nortriptyline would be sufficient for a patient who is a CYP2D6 poor metaboliser, an “ultra-rapid metaboliser” inheriting multiple copies of the gene would require a much higher daily dose to achieve the desired response.

Phenoconversion

Clinical problems may also arise from the co-administration of drugs that inhibit or compete for specific liver drug metabolising enzymes. A drug may interact with, and inhibit, CYP2D6 to the extent that it is no longer active, resulting in the patient responding like a poor metaboliser, even though they have a normal genetics metaboliser status. Such a phenomenon is known as phenoconversion. Thus, paroxetine, a powerful CYP2D6 inhibitor, may exaggerate the effects of other drugs that are prescribed together.

Not Just Liver Metabolism

Although individual genetic differences in drug metabolising enzymes are important, when it comes to psychotropic medications that act on the brain (eg antidepressants and antipsychotics) genetic differences in the molecules that carry drugs across the blood-brain barrier and into the brain, also play an important role.

Incite Genomics provides pharmacogenomic panels covering a range of genes involved in both liver metabolism and transportation of drugs into the brain.

Better, Safer Drugs the First Time.    

Instead of conventional trial and error of matching patients with the right drugs, doctors are now able to analyse a patient’s genetic profile and select the best available drug therapy from the beginning. 

This will speed up the recovery and increase safety as the likelihood of adverse reactions is reduced. A recent study published in the Lancet (1) showed that pharmacogenomic testing performed first to help guide medication selection reduced the number of unwanted adverse drug reactions by 30%.

Similarly, our scientists demonstrated (2) that using blood-brain barrier genetics in conjunction with the genetics of liver metabolism to select a patients antidepressant, resulted in 2.5 times more patients experiencing remission of their depression symptoms compared to those who were treated by conventional trial and error.

1 Lancet. 2023; 401: 347-356 2.   Clinical Psychopharmacology and Neuroscience 2015;13(2):150-156