A Report on How Pharmacist Contribute in Pharmacogenetics and Pharmacogenomics

Introduction

Pharmacogenetics and pharmacogenomics are the disciplines of broad interest that has greatly risen in recent years. They have become a prominent science that starting to impact significantly on clinical research and medical practice and contribute to a great application in drug development and therapeutics. Pharmacogenetics involves the study of single gene mutations and their effect on drug response.

Polymorphic variation in the genes that encode the functions of transporters, metabolizing enzymes, receptors, and other proteins can result in individual differences in the dose-plasma concentration response relationships for many important therapeutic agents [1]. For example, single nucleotide polymorphism (SNP), is a variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population.

In contrast, pharmacogenomics is a broader and newer based term that encompasses entire genome to assess several determinants of drug responses. Pharmacogenomics is thought to be the application of genomic technologies to the study of drug discovery, pharmacological function, disposition, and how an individual's genetic inheritance affects the body's response to drugs. This allows the use of genetic information to guide the choice of drug and dose on an individual basis. Pharmacogenomics intends to maximize drug efficacy, minimize drug toxicity, predict patients who will respond to intervention, aid in new drug development and to make treatment more personalized.

This new theory has the potential to make far-reaching changes in the practice of medicine and lead to an area of personalized medicine, in which drugs and drug combinations are optimized for each individual’s unique genetic makeup. The objective of the personalized medicine is to get the right dose of the right drug to the right patient at the right time.

Pharmacogenomic testing can identify variations in specific genes related to metabolizing or eliminating certain medications from the body. This can help in prescribing the right medication to get the best results with less trial and errors and to avoid side effects especially the life-threatening ones. It is available to predict how an individual may process and metabolize hundreds of different medications. There are many factors that can influence a person’s responses to medicine such as age, size of body, lifestyle, diet and state of health. This also includes the variation of genes as one of the major factors that cause the effects of drugs or medication can vary greatly between people.

To illustrate, genetic variations can influence the activity or have an effect of certain types of proteins. A drug that works for one person may not be as effective for others or may result in side effects as one size does not fit all. It is difficult to determine the efficacy of a medication in improving patient’s condition whether quickly, slowly or not helping at all. Therefore, pharmacogenomics can become the solution to solve the problem as it is relevant throughout a person’s lifetime as the effectiveness of medications and the increase risk of side effects can be identify and determine.

In order to achieve success in this new development, pharmacist who have always been the medication experts dealing with drug-drug interaction is needed to contribute in the pharmacogenetics and pharmacogenomics disciplines. Even the term pharmacogenomics comes from the words pharmacology and genomics and is thus the intersection of pharmaceuticals and genetics. Thus, pharmacist as the drug’s specialist plays a vital role to look at medication profile of each patient and help to interpret what needs to be changed. Adequate education, training, and practice-based resources are required to facilitate the development of sustainable pharmacist-led clinical pharmacogenomics practice models.

Major Role of Pharmacist in Pharmacogenetics and Pharmacogenomics Disciplines

Pharmacist has been known as an expert towards drug. They can function as walking pharmacopeia or MIMS because of the distinct knowledge they have for various drug’s pharmacology, pharmacokinetics and pharmacodynamics. As noted by Ed Abrahams, CEO of the Personalized Medicine Coalition (PMC) advocacy and education group, “[They] are on the front line of the actual prescribing,” he said, “and [this] will have to be individualized, based upon certain diagnostic tests in the future” [4]. Surge in drug research and development require pharmacist to learn along the new drugs ability and as increasing of century drugs nowadays are made personalized to the patient’s therapy to reduce or even made possible to no adverse event occur when drugs are taken by patient. Since many factors can alter drug pharmacokinetic, pharmacist play a role in tailoring medications to individuals to ensure the safety of patient and efficacy of drugs.

Prior to developing an indication for specific pharmacotherapy, in applying pharmacogenetics application, pharmacist have a fundamental responsibility to ensure that pharmacogenomic testing is performed when needed and that results are used to optimize medication therapy. Taking an example of carbamazepine, which has risk of life-threatening effect known as Stevens-Johnson syndrome and toxic epidermal necrolysis. Thus to make sure patient not encountering the scariest part of the adverse event, pharmacogenetic test need to be done to recommend this drug to the patient. HLA-B*1502 allele genotype need to be screened especially this allele is seen in high frequency in many Asian populations other than Han Chinese and increasing in mixed marriage contribute to the ability of the allele to even present in Caucasian which at first the association cannot be found. These made the application of pharmacogenetics and pharmacogenomics being utilize worldwide because test results will have implications throughout patient’s lifetime. Hence all pharmacist should have basic understanding of pharmacogenomic in order to interpret the clinical pharmacogenomic test results to provide appropriate patient-care recommendations.

As the expert in medicine, collaboration with the other health care professionals for example physician, laboratory professionals and genetic counselors is important in tailoring medications to individuals to ensure the safety of patient and efficacy of drugs. When results come out from the lab test which mainly will be provided by laboratory professional, pharmacist will screen prescribing medicine whether medicine prescribed are safe for the patient.

If one of the medicine prescribe is not suitable for the patient because of positive allele in patient that can contribute to the adverse event, pharmacist can give an advice to the prescriber to change the drug or regimen and providing a reason why drug prescribed is not suitable to the patient treatment. Some of the positive allele not only contribute to drug’s adverse event but also the efficacy of it. Besides, various patient with different metabolism ability will determine drug’s efficacious. Patient having ultra-rapid metabolism ability may need higher dose of medicine prescribed especially prodrug for it metabolites to exert an effect. Therefore, pharmacist is like a bridge for the healthcare professional and patient in providing accurate and reliable information for the treatment.

Last but not least, pharmacist need to be a forefront of education and knowledge about medication to patient as to ensure the safety of patient and efficacy of drugs. As the first line healthcare providers in communities, pharmacist must have clear knowledge and solid understanding regarding drugs and always use a right and effective language with patient to prevent misconceptions and wrong information. Apart from that, pharmacist should use their knowledge and expertise to educate medical providers. Explaining to clinicians regarding the benefits of a recommended treatment or drugs can ensure patients get the right tests and right medication, while expanding the provider knowledge base.

Example of The Major Role of Pharmacist in Pharmacogenomics and Pharmacogenetics Disciplines

Genes are found in all human cells which can influence a person’s response to medication. A basic gene may have many different forms and chemical messengers and they will show a different activity of the drugs towards the body. Thus, it is important in major role of the pharmacist to tailor the medication of individual to ensure the efficacy and safety of the medication through the use and aid of the pharmacogenetics and pharmacogenomics. First and foremost, clopidogrel is commonly prescribed for acute coronary syndrome because of its anti-platelet function.This agent transform into its active metabolites via hepatic biotransformation and this transformation will involve a predominant enzyme CYP2C19. It is stated that individual that carrying CYP2C19*2 and CYP2C19*3 allele will have reduced active clopidogrel metabolites formation and greater platelet aggregation in comparison with CYP2C19*1 homozygotes. [6] Thus, the individual which have this low allele function will have poor clopidogrel response and higher adverse effects. This statement also getting support and has been approved by U.S Food and Drug Administration (FDA). Thus, the pharmacists should suggest others anti-platelet agents such as prasugrel for individual that carrying CYP2C19*2 and CYP2C19*3 allele to prevent adverse effect meanwhile providing the desire anti-platelet effects.

Next, pharmacists should also be alert when prescribing warfarin. Warfarin is a definitive treatment worldwide for the long term prevention of cardiovascular as well as thromboembolic events. Although it is well known for its efficacy and almost in the market for 60 years, it still causes many side effects mainly due to its metabolism pathway. It is generally known that warfarin is metabolised by CYP2C9 enzyme. Therefore, it is a challenge for the pharmacist to manage the dosing of warfarin to avoid the severe adverse drug effects such as excessive bleeding. By using the pharmacogenetics and pharmacogenomics technology, the pharmacist could know that the patient whether is a fast drug metabolizer or slow drug metabolizer of the warfarin and make a correct decision on the dosing for the warfarin, ensuring the efficacy of the drug and avoiding any serious adverse effects. Patients who have the defects in the *2 and *3 allelic variants of the CYP2C9 need a lower maintenance of warfarin as they require longer time for dose stabilisation and have higher risk of serious bleeding compare with those normal patients.[7]

Beside the effects of cytochrome P-450 enzyme 2C9 (CYP2C9) on the metabolism of warfarin, pharmacist nowadays need to take another factor into consideration when adjusting the dosing for the warfarin. Recent pharmacogenetics and pharmacogenomics studies reveal that variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) affect the response to warfarin.[7] VKORC1 is responsible for recycling the reduced vitamin K, which is essential for the post-translational gamma-carboxylation of vitamin K–dependent clotting factors II, VII, IX, and X. Patients with this genotype in VKORC1 have reduced metabolism of warfarin. [8] Thus with the information provided from the pharmacogenomics and pharmacogenomics studies, the pharmacists should aware this and prescribe a lower dose of the warfarin to prevent risk of serious.

Another example for role of the pharmacist in ensuring the efficacy and reducing the adverse effects through the use pharmacogenetics and pharmacogenomics is when handling the prescription of metoprolol. Metoprolol is a beta-blocker and often used as anti-arrhythmic agents. This drug will undergo α-hydoxylation and O-demethylation and as a substrate of CYP2D6 enzyme. So, the genetic variation of the CYP2D6 enzyme will affect the pharmacokinetics of metoprolol. Despite the same doses of metoprolol administered by the patients, CYP2D6 poor metabolizers will have significantly higher metoprolol plasma concentrations and a prolonged half-life (t1/2) compared to other CYP2D6 phenotypes. [9] Thus, Dutch Pharmacogenetics Working Group (DPWG) guidelines recommends a reduced dose of metoprolol by 70-75% or change the drug to an alternative agent such as bisoprolol and carvedilol in these patients. As such, it is the duty of the pharmacists to take notes on the genetic result on the CYP2D6 in order to prevent the occurrence of adverse effect such as bradycardia and cold extremities caused by metoprolol.

Moreover, pharmacists could also use the information obtained from the pharmacogenetics and pharmacogenomics testing to suggest the clinicians when dealing with the psychiatric medications, ensuring that the patients have greatest improvements in their mental status without having serious adverse effects. If the patients have defects in the CYP 2C19 metabolism, the dose of numerous psychotropic drugs, including amitriptyline, citalopram, desimipramine, imipramine, sertraline, and diazepam should be lowered or even changes to another drugs to prevent the use of these drugs. Then, a genetic test done before the prescription of the psychotropic drugs can even help in the improvement of the sign and symptoms of the patients experienced due to the correct choice of drugs. For instance, sign and symptoms such as anxiety, depression, aggression, impulsive and impulsive showed more significant daily improvement after medication in tested patients compare to those do not undergone genetic test. [10]

Recommendation

Tailored drugs are based on patient’s individual uniqueness. By utilizing patients’ genetic and genomic information, healthcare can be provided from individual perspectives. This allows doctors to develop a more targeted treatment for patients. Tailored drugs provides great impact to our current healthcare society. Although it is proved that targeted therapies are beneficial, it is still not being integrated with our healthcare system because there are still many hindrance that we need to overcome before tailored drugs can be fully implemented. We have to make sure that healthcare providers are all aware with the tailored drugs initiative, well versed with the genetic and genomic content as that is the main concept of tailored drugs. This includes every person that involve in treating patients starts from person who diagnose the disease, determine which medication to be given, considering how each patients may respond to the medication in terms of safety and efficacy, also person who are responsible to deliver or administer the medications to patients.

First of all, before we want to provide any changes in current healthcare system, we need to expose and educate the healthcare providers as well as the society to make sure that they are aware with the concepts and benefits of tailored drugs. This is because the main challenges for the implementation of tailored drugs is lack of education and awareness among patients and healthcare providers. We can provide educational resources that provide all the basic scientific explanations of tailored drugs principles as well as technology-specific details that have been and being developed in ways that can be easily understood by society.[11] As for now, the most effective way is to publish this resources online because that is the most accessible platform for our current society who rely on the online information excessively. But, to ensure it success, it is our responsible to make sure that all the information provided are regularly updated, accurate and can be trusted as we do not want to educate or expose the society with the wrong information. Other than providing reading resources, we can also make a websites so that anyone can ask anything related to tailored drugs if they wanted to know more or have any doubt with tailored drug concepts.

As for the websites, we have to make sure that there is person in charged who will respond to all those questions as soon as possible and it is important that the person responding is the right person who really understand about tailored drugs so that they can provide answers in more appropriate ways. Although these strategies seems easy to be done, but building awareness and knowledge is not a thing that can be easily accomplished.[11] The effect of our strategies to build awareness is not something that can be seen in a week or two, it may probably take years for the society to get the idea of this tailored drug. To ensure that all healthcare providers’ knowledge about tailored drugs are up-to-date, healthcare system should provide them with adequate educational programs conducted by current genetic experts to make sure that they are all aware with the current medical concepts. Same goes to students in current medical and pharmacy school, they should be exposed to the updated medical concepts in their curricula so that they did not miss out.

Next, to utilize tailored drugs in our healthcare society, we can do a drug-gene testing to determine which treatment is the most appropriate treatment for that individual patient in terms of drug efficacy and safety as all patients do not respond to the same medicine similarly. Some patients may experience adverse effect that do not develop in other patients who takes the same drug at the same dose. Same goes to efficacy, drug may show different efficacy in different patients. All these varied response showed by individual patients are due to variability of our gene. Drug-gene testing can help to specifically identify how individuals’ gene affect body’s response to medications.

Each medications are associated with specific drug-gene test which looks for any variants in genes that may determine whether that medication is an effective medication or otherwise.[12] It uses the patients’ molecular information to better diagnose the disease and develop a more targeted therapies, to treat patients with more suitable treatment considering safety and efficacy of each individuals. Thus, this test help the healthcare providers to find out the most suitable medication to be given to individual patients.

Other than that, as tailoring drugs to individual patients use patients’ molecular information, patients have the right to protect their molecular information and know what is that information used for. So, to overcome this, if we want to implement tailored drugs in our healthcare system, patient should be allowed to be involve in deciding how their data are used, particularly in environment where treatment is managed by several numbers of specialists. Genetic counselling service should be provided by healthcare providers to ensure that patients understand their individual molecular information so that they are able to make appropriate decision without arising any possible problems. Patients should be regularly and appropriately involved in their healthcare decision making.[11]

Hence, it is possible for us to implement tailored drugs in our healthcare system if we slowly recognize all the challenges that may be the reason why it is impossible and try to overcome each one of them considerably. It is worth to try every available mean to implement tailored drugs as its benefits can be clearly seen.

Conclusion

In conclusion, pharmacist have a responsibility to take an outstanding role in the clinical application of pharmacogenomics and pharmacogenetics. Tailoring medications to individuals in order to ensure the safety and efficacy of the drugs toward the patient, is one of the major role that pharmacist can contribute in pharmacogenomics and pharmacogenetics discipline. Pharmacist are expert in helping patients get the most out of today’s complicated medications especially when it comes to the issues of their unwanted adverse effect, efficacy and safety of the drug to the patients. In order to promote safety, effective and cost-effective medication practises, this emerging science should be prompt in many institutions by all of the pharmacists.[13]

From the surveyed that has been done, pharmacists themselves perceived them as lacking confidence and educational background in pharmacogenomics and pharmacogenetics. In fact, they are the most important person that plays a important major role contributing to this disciplines. If pharmacists are to become leaders in this age of personalized medicine, they must be prepared to make recommendations regarding pharmacogenomics testing, successfully interpret and apply results for pharmacogenomics-driven therapeutic decisions, and teach pharmacogenomics to other healthcare providers.[14]

Most drugs were designed to work on the population level rather than being targeted for the individual patient in the past. The trend can be reversed to refine the focus of treatment and makes drugs more effective and less toxic by a pharmacogenomics and pharmacogenetics benefits. Pharmacogenomic and pharmacogenetics practice examines and treats the genotype rather than relying on the outward manifestation of disease the signs and symptoms that physicians call the phenotype. Thus, many potential drugs which may be lost due to the effects on the outliers in a study can be retained when pharmacogenomics and pharmacogenetics study is used in the clinical practice.