Physicians will soon foretell whether a patient is likely to suffer or benefit from a specific drug with the option of Pharmacogenomics and personalized medicine.
As medical professionals prescribe more and more drugs with a narrow therapeutic window, traditional approaches to how such therapies are monitored need to be replaced with modern tools such as Pharmacogenomics.
The foundation of personalized medicine is built on using an individual's genetic profile to conclude upon the best therapeutic choice by allowing predictions about whether that person will benefit from a specific medicine or suffer serious side effects. Drugs are by and large tested on a large population of people and the average response is reported. This kind of evidence-based medicine (which is, medical decision making based on empirical data) rests on the law of averages; personalized medicine, on the other hand, recognizes that no two patients are alike.
Going deeper into the traditional approach to medicine, it is basically based on iterative one size fits all protocols. The more medically appropriate way to express this would be that our protocols are based around therapeutic drug monitoring (TDM), which is also at times referred to as therapeutic drug management. In a nutshell this approach entails maximising the efficacy while minimising toxicity. Some examples of drugs that are monitored using this principle include Aminoglycoside antibiotics (gentamicin), Antiepileptics (such as carbamazepine, phenytoin and valproic acid), Mood stabilisers, especially lithium citrate, Antipsychotics (such as pimozide and clozapine), Biologic monoclonal antibody drugs (such as adalimumab, certolizumab pegol and infliximab) and many more.
What has made TDM imperative?
There are a multitude of reasons that has made therapeutic drug monitoring (TDM) necessary as drugs with specific therapeutic window began to be administered.
Some of these reasons include the fact that these drugs have a narrow range of safe and effective dosage, potential patient compliance issues and optimisation of drug dosage cannot be based on just clinical observation. Historically drug dosage has been driven by a reliance on average population responses. However with a country as diverse as India , there is no real average and even a slight deviation from average results in either no drug efficacy at best or toxicity at worst for hundreds of thousands if not millions. Genotyping and other genomics related offerings provide us with the ability to provide information specific to an individual’s drug response.
Basics of Pharmacogenomics
In the field of Pharmacogenomics, genomic information is utilized to understand individual responses to drugs. When a gene variant is linked with a specific drug response in a patient, there is the likely-hood for making clinical decisions resting on genetics by regulating the dosage or preferring to choose or opt for a different drug, for example. Scientists assess gene variants affecting an individual's drug response the same way they assess gene variants associated with diseases: by identifying genetic loci related with known drug responses, and then testing persons whose response is unknown. Contemporary approaches comprise multi-gene analysis or whole-genome single nucleotide polymorphism (SNP) profiles, and these approaches are just coming into clinical use for drug innovation and progress.
While analysing and studying drug reaction in individuals, researchers typically emphasize on two major determinants: (1) how much quantity of the drug is required to reach its objective in the body, and (2) how well the indented or the target cells, such as heart tissue or neurons, act in response to the drug. The scientific terms for these two determinants are pharmacokinetics and pharmacodynamics, and both are critical considerations in the field of pharmacogenomics.
Understanding Pharmacokinetic and Pharmacodynamic
At a technical level mastering Pharmacokinetic and Pharmacodynamic principles is critical to understanding the role of genomics in determining drug therapy and drug dosage, i.e. the field of Pharmacogenomics.
Pharmacokinetics takes into consideration four processes: absorption, distribution, metabolism, and excretion, which are often referred as as ADME. Absorption usually means how a drug enters the bloodstream after a person takes a pill or uses an inhalant; intravenous injection circumvents absorption by putting a drug directly into the blood. Distribution refers to where the drug travels after absorption and how much of the drug reaches the intended or the target site. Many drugs, for example, cannot get past the blood-brain barrier. Metabolism refers to how the drug gets broken down in the body, which can take place straight away by way of enzyme action in the stomach and at times involves end products with their own pharmacologic action. Ultimately, excretion refers to how drugs exit the body, whether it is by urine, bile, or, in some cases, exhalation.
Pharmacodynamics entails a whole body of work around receptor occupancy theory which starts with the drug’s action on a target cell but also includes the affinity of the receptor to the drug. Genetic factors are the driving force for both of these principles but until recently the only way to monitor these principles was via iterative therapeutic drug monitoring. Genetic variants or polymorphisms in the promoter region of a gene expressing the receptor protein may affect the number of receptors. Genetic variants in the coding region would impact the affinity of the same receptors.
Receptor protein status cannot be determined by either measuring concentration of drug in the blood stream or via TDM (because it is an iterative process that begins with drug dosage). Genotyping and other genomics based approaches allows clinicians to determine drug selection and drug dosage specific to the receptivity of an individual patient. This ability to determine the drug and its dosage without any iteration has several benefits including minimising potential toxicity, reducing adjustments in dosage, optimising drug efficacy and also avoiding drug-drug interactions. A key driver of Pharmacogenomics and the precision medicine it entails is in research as we need to discover/validate the variants in the Indian populations and not simply use the data from caucasian studies . This will entail Indian Genome-wide association studies from Indian subcontinent for most common drugs prescribed here. Over the last decade Indian institutes including Centre for Cellular & Molecular Biology (CCMB), CSIR-Institute of Genomics and Integrative Biology (IGIB) , Indian Institute of Science (IISc), National Institute of Biomedical Genomics (NIBMG), Tata Memorial Hospital(TMH-ACTREC) and private labs such as such as Strand-HCG, Medgenome, GenepathDx, Sandor and many more are driving research and clinical projects in this field.
What is important here is to develop a database of genetic variants in the Indian populations and not blindly use data from caucasian studies for Pharmacogenomics.
The field of Pharmacogenomics is still in its infancy in terms of drug discovery. Its use is currently limited to the few areas on which researchers and clinicians have been able to identify the genetic variations responsible for drug receptivity. However new approaches are under study in clinical trials. We are not too far away from a day when Pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, neurodegenerative disorders, cancer, HIV/AIDS, and asthma.
Challenges of pharmacogenomics
Even though pharmacogenomics is to be expected to be an important part of future medical care, there are many obstructions to triumph over before it becomes routine:
- When associations between a genetic variant and a drug response
- have been clearly demonstrated, suitable tests still needs to be developed and proved to be effective in clinical trials.
- A test that has been successful in a clinical trial still has to be shown to be useful and cost-effective in a healthcare setting.
- Regulatory agencies will have to think over as to how they should assess and license pharmacogenetic products.
- Health services will have to bend to new ways of arriving at the best drug to give to an individual.
- The behaviour of individual doctors will need to change.
Some examples of pharmacogenomics working effectively, for example abacavir and HIV, show that these challenges can sometimes be overcome.
(The author is Executive Director of Premas Life Sciences)