PHARMACOGENOMICS: DRUG INTOLERANCES AND GENES

August 07, 2018 10:00 pm

Pharmacogenomics, Alison Vickery, Health, Australia
When you look in the dictionary under “drug intolerances and genes,” you will find my name.

Firstly, I have written widely about adverse drug reactions’ effects on my health.

It all started with being prescribed Metformin®, a medication for insulin resistance, resulting in my diagnosis of histamine intolerance.

Subsequently, a series of severe adverse reactions to medications saw me diagnosed with mast cell activation, chronic fatigue syndrome, sub-clinical Cushing’s Syndrome, and an acquired brain injury.

That is, the mast-cell activation diagnosis was due to drug intolerances. Specifically, having less than 20% function of the CYP2D6 gene, meaning medicines that utilize this gene are toxic to me, causing drug intolerances.

However, a new world of pharmacogenomics has changed that, making essential medicines available to me.

Pharmacogenomics is the branch of medicine that predicts an individual’s response to medicines before they take them, thereby reducing the risk of drug intolerances.

It takes the guesswork out of the right medicine in the correct dose for the individual, significantly minimizing the chance of drug intolerances.

While many factors can affect medicine safety, pharmacogenomics is often overlooked and yet profoundly impacts medicine safety.

This is why it matters.

pharmacogenomics, drug intolerances, drug intolerance testing

Personalised Medicine: Overcoming Drug Intolerances

Current Australian prescribing guidelines adopt a “one size fits all” model.

However, medical scientists, drug companies, and regulators have known for decades that any given medicine is only effective in 60 to 70% of people. Furthermore, antidepressants and statins have significantly worse outcomes than this, often due to drug intolerances.

For instance, Dr. Allen Roses of Glaxo Smith Kline has even stated that:

“The vast majority of drugs – more than 90 percent – only work in 30 or 50 percent of the people,”

“I wouldn’t say that most drugs don’t work. I would say that most drugs work in 30 to 50 percent of people. Drugs on the market work, but they don’t work in everybody.”

Simplistically, despite a system that works on “averages,” there are not many averages, such that the “quality use of medicines” needs to consider the individual to prevent drug intolerances.

Unfortunately, current Australian prescribing practices do not consider the individual. One of the main ways to consider the individual is through pharmacogenomic testing, which can significantly reduce the incidence of drug intolerances.

Therefore, by incorporating pharmacogenomic testing, we can move away from a one-size-fits-all approach and better prevent drug intolerances, ensuring medicines are safer and more effective for everyone.

Pharmacogenomics, Drug Intolerances

When Medications Backfire: Identifying Drug Intolerances

This law of average approach also has several other problems. 

Firstly, when a medicine does not act as intended, increasing the dosage or adding additional medicine is standard practice. This approach is guesswork.

For instance, the dosage might be too high, not too low, for the individual. Alternatively, the individual might be unable to use the medicine effectively because they have too little function in the relevant metabolic pathway, and alternative medicine might work better and prevent drug intolerances.

Moreover, additional medicines can interact, a situation called poly-pharmacy. With every additional medicine, this risk of drug intolerances increases, particularly with over two medications.

Additionally, it is often difficult to stop a medicine, which can further complicate drug intolerances.

Whenever a medicine does not act as designed, for example, painkillers do not address our pain, or antidepressants make us even more depressed, we need to consider pharmacogenomics.

Furthermore, all medicines have risks. For example, in June 2018, the Therapeutic Goods Administration warned that a significant number of medications cause severe adverse reactions, including suicide. 

This includes a broad range of antidepressants, attention deficit hyperactivity disorder medications, seasonal allergy medicines, smoking cessation medicines, and acne medicines.  

Could this be due to pharmacogenomics? 

Notably, one study showed that patients who metabolize medicines very slowly or very quickly have four times more disability claims than those with typical pharmacogenomic test results.

Therefore, it seems to me to be barbaric to prefer to guess whether the drug will be tolerated, particularly for high-risk medicines that cannot simply be withdrawn.

What if your doctor determined the right medicine and dosage from the start? What if the wrong medicine in the wrong dosage led to a permanent disability due to drug intolerances?

Pharmacogenomics: Minimizing Drug Intolerances Through Precision Medicine

The quality use of medicine demands that the individual be taken into account. To achieve this, pharmacogenomics considers the individual and their potential drug intolerances.

Firstly, an individual’s genes (mainly four essential genes—CYP2D6, CYP2C19, CYP2C9, and CYP3A4) determine how an individual will respond to medicines.

These four genes process approximately 80% of all medicines, making them critical in understanding drug intolerances.

Moreover, they are highly variable among people, including specific ethnic groups. Therefore, drug response and drug intolerances vary significantly by race.

Depending on the activity of these genes, the medicine works, does not work, or causes severe adverse drug reactions, if not long-term disability due to toxicity.

For example, around 10% of Caucasians are at severe risk of hospitalisation, death, and disability if given the “average” dose of certain medicines due to drug intolerances. 

Furthermore, 40% need a higher or lower dose to get the desired effects, considering their potential drug intolerances.

Additionally, the risk of drug intolerance is significantly higher in other ethnic groups, including Asians, Pacific Islanders, and Africans. Approximately 70% (rather than 10%) are at risk if given the “average” dose. 

The pharmacogenomic makeup of descendants of Aboriginal persons is currently subject to a detailed study to understand their specific drug intolerances.

Therefore, please consider getting tested if your paternal or maternal family has a history of drug intolerances.

But why stop there?

Furthermore, the test has a lifelong application. What if all children were tested at birth to get the right medicine in the correct dose throughout their lives? It seems a small price to pay.

Genetic Testing: A Key Tool in Preventing Drug Intolerances

Several pathology companies now provide genetic testing for how people react to drugs to prevent drug intolerances including:

  • Firstly, myDNA – this is who I used.
  • Additionally, Genesight – in the USA.

However, it is essential to note that 23andMe does not report the relevant genes due to regulatory limitations.

Moreover, two key bodies have been working to develop pharmacogenomics recommendations based on these test results.

Firstly, the Pharmacogenetic Working Group of the Royal Dutch Association for the Advancement of Pharmacy (DPWG) has incorporated recommendations into the National Dutch electronic prescribing system. This system is being introduced in other European countries and is significantly reducing drug intolerances.

Secondly, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has systematically reviewed and incorporated recommendations into the guidelines of the United States Food and Drug Administration, aiming to mitigate drug intolerances.

Importantly, these guidelines are evidence-based, and there are now a growing number of double-blind trials showing better health outcomes and significant reductions in health costs by using pharmacogenomics to inform decisions and reduce drug intolerances.

Conclusion

In conclusion, embracing pharmacogenomics is a game-changer for personalized medicine and preventing drug intolerances.

By understanding our genetic makeup, we can predict how our bodies will respond to various medications, ensuring that treatments are effective and safe.

This approach not only enhances individual health outcomes but also significantly reduces the risk of adverse drug reactions and long-term disabilities.

With the availability of genetic testing and the support of evidence-based guidelines from reputable bodies like DPWG and CPIC, we are now better equipped than ever to tailor medical treatments to our unique genetic profiles.

Consequently, this revolution in healthcare promises a future where drug intolerances are minimized, and the right medicine at the right dose becomes the standard of care.

Therefore, whether you’re dealing with chronic conditions or simply aiming for optimal health, consider the power of pharmacogenomics.

It could be the key to unlocking a healthier, more personalized approach to medicine for you and your loved ones.

Let’s move beyond the one-size-fits-all model and embrace the future of individualized healthcare.

Additional Reading

Australian Centre for Health Research, Improving the Quality Use of Medicines in Australia, Realising the Potential of Pharmacogenomics, October 2008.

Deloitte, 2007, Targeted Therapies: Navigating the Business Challenges of Personalised Medicine, Deloitte Centre for Health Solutions, p 6.

Australian Centre for Health Research, Improving the Quality Use of Medicines in Australia, Realising the Potential of Pharmacogenomics, October 2008.

https://acola.org.au/wp/pmed/

https://cpicpgx.org/guidelines/ and https://www.pharmgkb.org/guidelines

https://www.tga.gov.au/publication-issue/medicines-safety-update-volume-9-number-2-june-2018#a2

Winner JG, Carhart JM, Altar CA, Allen JD, Dechairo BM. A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Discov Med. 2013;16(89):219-27.

Singh AB. Improved Antidepressant Remission in Major Depression via a Pharmacokinetic Pathway Polygene Pharmacogenetic Report. Clin Psychopharmacol Neurosci. 2015;13(2):150-6.

Perez V, Salvart A, Espadeler J, et. al. Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder results of a randomized, double-blind clinical trial. BMC Psychiatry. 2017;17:250.

Elliott LS, Henderson JC, Neradilek MB, Moyer NA, Ashcraft KC, Thirumaran RK. Clinical impact of pharmacogenetic profiling with a clinical decision support tool in polypharmacy home health patients: A prospective pilot randomized controlled trial. PLoS One. 2017;12(2):e0170905.

Saldivar JS, Taylor D, Sugarman EA, Cullors A, Garces JA, Oades K, et al. Initial assessment of the benefits of implementing pharmacogenetics into the medical management of patients in a long-term care facility. Pharmacogenomics Pers Med. 2016;9:1-6.

Bradley P, Shiekh M, Mehra V, et al.: Improved efficacy with targeted pharmacogenetic-guided treatment of patients with depression and anxiety: a randomized clinical trial demonstrating clinical utility. J Psychiatr Res 2017; 96:100–10.