Pharmacogenomics aims to predict three major drug effects: Efficacy (how effectively a drug works), toxicity (potential side effects and ways to negate), dosing (optimal dose of drug to administer to patients).
- Efficacy – “How effectively the drug works based on the patient’s medical condition and genetic makeup?”
- Toxicity – “What are the potential side effects of this drug, and how can we minimize its adverse effects for the patient?”
- Dosing – “How can we ensure the administration of the optimal dosage while minimizing the risk of overdose?”
Active Drugs and Prodrugs
Individual genetic makeup influence how their body metabolize the drugs, which impact drug efficacy and the risk of side effects.
- Normal metabolism ↠requires the normal dose of drug
- Fast metabolism ↠requires more dose of drug
- Slow metabolism ↠requires less dose of drug
Many drugs are inactivated through metabolism. However, Phase I and II metabolism also led to activation of drugs metabolite. It activated an administered inactive drug. E.g., codeine to morphine.
Codeine is prodrugs which converted from inactive form to active form through metabolism process. The active form of codeine is morphine which provides its pain-relieving therapeutic effects.
Individual genetic makeup influence how their body metabolize the prodrugs, which impact drug efficacy and the risk of side effects.
Phenotype relationship with Genotype
Genetic variations defined into four different types of phenotypes based the functional status of the genetic variants and its impact on enzyme activity in terms of degree of drug response: poor, intermediate, extensive and ultrarapid metabolizers for a specific gene/drug pair.
Adverse drug reactions
Pharmacogenomics which works to address Adverse Drug Reactions is known as safety pharmacogenomics.
World Health Organization defined that Adverse drug reaction (ADR) is major cause of hospitalization and death which excludes overdoses and errors. Adverse drug reaction (ADR) is around 6% of all hospital admissions.
In 1990s, a large-scale survey suggested that ADR ranked as fourth to sixth most common causes of death among inpatient mortality in US and follow-up survey in 2010 showed no improvement. In Canada, ADR is fourth most common causes of death.
As 2019 study, ADR have been identified as a significant contributor in hospital admissions account for 6.5% of all hospitalizations at two largest hospitals in UK.
Challenges
Privacy and Ethical concerns – The Utilization of genetic information in healthcare also raises concerns about privacy, ethical issues surrounding genetic information and the potential for genetic as well as racial discrimination. E.g., 23andme data breach
For example, questions raised on Bupa where it stored the genetic data and who are able to access it. Bupa clarified that it stored with any other part of Bupa.
Lack of diverse population data such as studies had targeted predominately European and American populations limiting interpretation of findings.
Achieving reproducibility of results continues to be significant challenge. Requires robust methods to harmonize data across studies.
Limitations
Lack Training and Knowledge – Healthcare providers lack training & knowledge to interpret and apply test results in patient care. Clinicians lack how to interpret, utilize them for therapy, dose selection or take therapeutic decisions. The lack of knowledge was the main factor behind the slow adoption of pharmacogenomics.
Evolving pharmacogenomics – our understanding of how genetics affects our response to drugs is still limited.
Pharmacogenomics guidelines
Scientific guidelines and statements from consortiums such as the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Pharmacogenomics Knowledge Base (PharmGKB), PharmVar, and the American Heart Association (AHA), along with FDA approvals for specific gene–drug interactions, have driven the development of more clinical pharmacogenomic (PGx) tests.
