Pharmacogenomics

Pharmacogenomics was first recognized by Pythagoras around 510 BC when he made a connection between the dangers of fava bean ingestion with hemolytic anemia and oxidative stress. This identification was later validated and attributed to deficiency of G6PD in the 1950s and called favism.[11][12] Although the first official publication dates back to 1961,[13] circa 1950s marked the unofficial beginnings of this science. Reports of prolonged paralysis and fatal reactions linked to genetic variants in patients who lacked butyryl-cholinesterase ('pseudocholinesterase') following administration of succinylcholine injection during anesthesia were first reported in 1956.[2][14] The term pharmacogenetic was first coined in 1959 by Friedrich Vogel of Heidelberg, Germany (although some papers suggest it was 1957 or 1958).[15] In the late 1960s, twin studies supported the inference of genetic involvement in drug metabolism, with identical twins sharing remarkable similarities to drug response compared to fraternal twins.[16] The term pharmacogenomics first began appearing around the 1990s.[11]

The first FDA approval of a pharmacogenetic test was in 2005[9] (for alleles in CYP2D6 and CYP2C19).

The term pharmacogenomics is often used interchangeably with pharmacogenetics. Although both terms relate to drug response based on genetic influences. Pharmacogenetics encompasses a more genome-wide association approach, incorporating genomics and epigenetics while dealing with the effects of multiple genes or even chromosomes on drug response.[6][17][18] Pharmacogenetics study the inherited genetic differences in drug metabolic pathways (and other pharmacological principles, like enzymes, messengers and receptors) which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects.[19] Pharmacogenomics in the other hand focuses on single drug-gene interactions taking in count allele genes, dominance and gene polymorphism in order to understand the better use of a drug on a single patient or population.

There are several known genes which are largely responsible for variances in drug metabolism and response. The focus of this article will remain on the genes that are more widely accepted and utilized clinically for brevity.

• Cytochrome P450s
• VKORC1
• TPMT

Pharmacogenetic panels are used to analyze and detects changes in multiple genes that are involved in the drug metabolism allowing clinicians to select the most appropriate medications and dosages for their patients, among the companies that offer these panels can be named the following:

• Mayo Clinic: Focused pharmacogenomics panel or PGXQP.[38]
• Quest Diagnostics: QuestPGx.
• Paragon Genomics: CleanPlex NGS Panels
• Invitae

Patient genotypes are usually categorized into the following predicted phenotypes:

• UM: Ultra-rapid metabolizer: patients with substantially increased metabolic activity;
• EM: Extensive metabolizer: normal metabolic activity;
• IM: Intermediate metabolizer: patients with reduced metabolic activity; and
• PM: Poor metabolizer: patients with little to no functional metabolic activity.

The two extremes of this spectrum are the poor metabolizers and ultra-rapid metabolizers. Efficacy of a medication is not only based on the above metabolic statuses, but also the type of drug consumed. Drugs can be classified into two main groups: active drugs and prodrugs. Active drugs refer to drugs that are inactivated during metabolism, and prodrugs are inactive until they are metabolized.

An overall process of how pharmacogenomics functions in a clinical practice. From the raw genotype results, this is then translated to the physical trait, the phenotype. Based on these observations, optimal dosing is evaluated.[36]

For example, we have two patients who are taking codeine for pain relief. Codeine is a prodrug, so it requires conversion from its inactive form to its active form. The active form of codeine is morphine, which provides the therapeutic effect of pain relief. If person A receives one *1 allele each from mother and father to code for the CYP2D6 gene, then that person is considered to have an extensive metabolizer (EM) phenotype, as allele *1 is considered to have a normal-function (this would be represented as CYP2D6 *1/*1). If person B on the other hand had received one *1 allele from the mother and a *4 allele from the father, that individual would be an Intermediate Metabolizer (IM) (the genotype would be CYP2D6 *1/*4). Although both individuals are taking the same dose of codeine, person B could potentially lack the therapeutic benefits of codeine due to the decreased conversion rate of codeine to its active counterpart morphine.

Each phenotype is based upon the allelic variation within the individual genotype. However, several genetic events can influence a same phenotypic trait, and establishing genotype-to-phenotype relationships can thus be far from consensual with many enzymatic patterns. For instance, the influence of the CYP2D6*1/*4 allelic variant on the clinical outcome in patients treated with Tamoxifen remains debated today. In oncology, genes coding for DPD, UGT1A1, TPMT, CDA involved in the pharmacokinetics of 5-FU/capecitabine, irinotecan, 6-mercaptopurine and gemcitabine/cytarabine, respectively, have all been described as being highly polymorphic. A strong body of evidence suggests that patients affected by these genetic polymorphisms will experience severe/lethal toxicities upon drug intake, and that pre-therapeutic screening does help to reduce the risk of treatment-related toxicities through adaptive dosing strategies.[39]

The list below provides a few more commonly known applications of pharmacogenomics:[40]

• Improve drug safety, and reduce ADRs;
• Tailor treatments to meet patients' unique genetic pre-disposition, identifying optimal dosing;
• Improve drug discovery targeted to human disease; and
• Improve proof of principle for efficacy trials.

Pharmacogenomics may be applied to several areas of medicine, including pain management, cardiology, oncology, and psychiatry. A place may also exist in forensic pathology, in which pharmacogenomics can be used to determine the cause of death in drug-related deaths where no findings emerge using autopsy.

In cancer treatment, pharmacogenomics tests are used to identify which patients are most likely to respond to certain cancer drugs. In behavioral health, pharmacogenomic tests provide tools for physicians and care givers to better manage medication selection and side effect amelioration. Pharmacogenomics is also known as companion diagnostics, meaning tests being bundled with drugs. Examples include KRAS test with cetuximab and EGFR test with gefitinib. Beside efficacy, germline pharmacogenetics can help to identify patients likely to undergo severe toxicities when given cytotoxics showing impaired detoxification in relation with genetic polymorphism, such as canonical 5-FU.[41] In particular, genetic deregulations affecting genes coding for DPD, UGT1A1, TPMT, CDA and CYP2D6 are now considered as critical issues for patients treated with 5-FU/capecitabine, irinotecan, mercaptopurine/azathioprine, gemcitabine/capecitabine/AraC and tamoxifen, respectively.[42]

In cardiovascular disorders, the main concern is response to drugs including warfarin, clopidogrel, beta blockers, and statins.[10] In patients with CYP2C19, who take clopidogrel, cardiovascular risk is elevated, leading to medication package insert updates by regulators.[43] In patients with type 2 diabetes, haptoglobin (Hp) genotyping shows an effect on cardiovascular disease, with Hp2-2 at higher risk and supplemental vitamin E reducing risk by affecting HDL.[44]

In psychiatry, as of 2010, research has focused particularly on 5-HTTLPR and DRD2.[45]

Case A – Antipsychotic adverse reaction[55]

Patient A has schizophrenia. Their treatment included a combination of ziprasidone, olanzapine, trazodone and benztropine. The patient experienced dizziness and sedation, so they were tapered off ziprasidone and olanzapine, and transitioned to quetiapine. Trazodone was discontinued. The patient then experienced excessive sweating, tachycardia and neck pain, gained considerable weight and had hallucinations. Five months later, quetiapine was tapered and discontinued, with ziprasidone re-introduction into their treatment due to the excessive weight gain. Although the patient lost the excessive weight they gained, they then developed muscle stiffness, cogwheeling, tremors and night sweats. When benztropine was added they experienced blurry vision. After an additional five months, the patient was switched from ziprasidone to aripiprazole. Over the course of 8 months, patient A gradually experienced more weight gain, sedation, developed difficulty with their gait, stiffness, cogwheeling and dyskinetic ocular movements. A pharmacogenomics test later proved the patient had a CYP2D6 *1/*41, which has a predicted phenotype of IM and CYP2C19 *1/*2 with a predicted phenotype of IM as well.

Case B – Pain Management[56]

Patient B is a woman who gave birth by caesarian section. Her physician prescribed codeine for post-caesarian pain. She took the standard prescribed dose, however experienced nausea and dizziness while she was taking codeine. She also noticed that her breastfed infant was lethargic and feeding poorly. When the patient mentioned these symptoms to her physician, they recommended that she discontinue codeine use. Within a few days, both the patient and her infant's symptoms were no longer present. It is assumed that if the patient underwent a pharmacogenomic test, it would have revealed she may have had a duplication of the gene CYP2D6 placing her in the Ultra-rapid metabolizer (UM) category, explaining her ADRs to codeine use.

Case C – FDA Warning on Codeine Overdose for Infants[57]

On February 20, 2013, the FDA released a statement addressing a serious concern regarding the connection between children who are known as CYP2D6 UM and fatal reactions to codeine following tonsillectomy and/or adenoidectomy (surgery to remove the tonsils and/or adenoids). They released their strongest Boxed Warning to elucidate the dangers of CYP2D6 UMs consuming codeine. Codeine is converted to morphine by CYP2D6, and those who have UM phenotypes are at danger of producing large amounts of morphine due to the increased function of the gene. The morphine can elevate to life-threatening or fatal amounts, as became evident with the death of three children in August 2012.

The U.S. Food and Drug Administration (FDA) appears to be very invested in the science of pharmacogenomics[58] as is demonstrated through the 120 and more FDA-approved drugs that include pharmacogenomic biomarkers in their labels.[59] This number increased varies over the years.[60] A study of the labels of FDA-approved drugs as of 20 June 2014 found that there were 140 different drugs with a pharmacogenomic biomarker in their label.[61] Because a drug can have different biomarkers, this corresponded to 158 drug–biomarker pairs.[61]

Only 29% stated a requirement or recommendation for genetic biomarker testing but this was higher for oncology drugs (62%).[61] On May 22, 2005, the FDA issued its first Guidance for Industry: Pharmacogenomic Data Submissions, which clarified the type of pharmacogenomic data required to be submitted to the FDA and when.[62] Experts recognized the importance of the FDA's acknowledgement that pharmacogenomics experiments will not bring negative regulatory consequences.[63] The FDA had released its latest guide Clinical Pharmacogenomics (PGx): Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling in January, 2013. The guide is intended to address the use of genomic information during drug development and regulatory review processes.

Consecutive phases and associated challenges in Pharmacogenomics.[64]

Although there appears to be a general acceptance of the basic tenet of pharmacogenomics amongst physicians and healthcare professionals,[65] several challenges exist that slow the uptake, implementation, and standardization of pharmacogenomics. Some of the concerns raised by physicians include:[18][65][66]

• Limitation on how to apply the test into clinical practices and treatment;
• A general feeling of lack of availability of the test;
• The understanding and interpretation of evidence-based research;
• Combining test results with other patient data for prescription optimization; and
• Ethical, legal and social issues.

Issues surrounding the availability of the test include:[64]

• The lack of availability of scientific data: Although there are considerable number of DME involved in the metabolic pathways of drugs, only a fraction have sufficient scientific data to validate their use within a clinical setting; and
• Demonstrating the cost-effectiveness of pharmacogenomics: Publications for the pharmacoeconomics of pharmacogenomics are scarce, therefore sufficient evidence does not at this time exist to validate the cost-effectiveness and cost-consequences of the test.

Although other factors contribute to the slow progression of pharmacogenomics (such as developing guidelines for clinical use), the above factors appear to be the most prevalent. Increasingly substantial evidence and industry body guidelines for clinical use of pharmacogenetics have made it a population wide approach to precision medicine. Cost, reimbursement, education, and easy use at the point of care remain significant barriers to widescale adoption.

Some alleles that vary in frequency between specific populations have been shown to be associated with differential responses to specific drugs. The beta blocker atenolol is an anti-hypertensive medication that is shown to more significantly lower the blood pressure of Caucasian patients than African American patients in the United States. This observation suggests that Caucasian and African American populations have different alleles governing oleic acid biochemistry, which react differentially with atenolol.[67] Similarly, hypersensitivity to the antiretroviral drug abacavir is strongly associated with a single-nucleotide polymorphism that varies in frequency between populations.[68]

The FDA approval of the drug BiDil (isosorbide dinitrate/hydralazine) with a label specifying African-Americans with congestive heart failure, produced a storm of controversy over race-based medicine and fears of genetic stereotyping,[69] even though the label for BiDil did not specify any genetic variants but was based on racial self-identification.[70][71]

Computational advances have enabled cheaper and faster sequencing.[72] Research has focused on combinatorial chemistry,[73] genomic mining, omic technologies and high throughput screening.

As the cost per genetic test decreases, the development of personalized drug therapies will increase.[74] Technology now allows for genetic analysis of hundreds of target genes involved in medication metabolism and response in less than 24 hours for under $1,000. This a huge step towards bringing pharmacogenetic technology into everyday medical decisions. Likewise, companies like deCODE genetics, MD Labs Pharmacogenetics, Navigenics and 23andMe offer genome scans. The companies use the same genotyping chips that are used in GWAS studies and provide customers with a write-up of individual risk for various traits and diseases and testing for 500,000 known SNPs. Costs range from $995 to $2500 and include updates with new data from studies as they become available. The more expensive packages even included a telephone session with a genetics counselor to discuss the results.[75]

Pharmacogenetics has become a controversial issue in the area of bioethics. Privacy and confidentiality are major concerns.[76] The evidence of benefit or risk from a genetic test may only be suggestive, which could cause dilemmas for providers.[76]^: 145 Drug development may be affected, with rare genetic variants possibly receiving less research.[76] Access and patient autonomy are also open to discussion.[77]^: 680

• Genomics
  • Chemogenomics
  • Clinomics
  • Genetic engineering
  • Toxicogenomics
  • Cancer pharmacogenomics
• Metabolomics
• Pharmacovigilance
• Population groups in biomedicine
• Toxgnostics
• Medical terminology
  • LOINC
  • SNOMED CT
  • HPO
  • HGVS
• HL7
  • FHIR

• Genetic testing

• "Pharmacogenomics Factsheet". National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine. Retrieved 2011-07-11. a quick introduction to customised drugs
• "Pharmacogenomics Education Initiatives". U.S. Food and Drug Administration. 2010-09-24. Retrieved 2011-07-11.
• "Personalized Medicine (Pharmacogenetics)". University of Utah's Genetic Science Learning Center. Archived from the original on 2011-05-19. Retrieved 2011-07-11.
• "Center for Pharmacogenomics and Individualized Therapy". University of North Carolina at Chapel Hill Center for Pharmacogenomics and Individualized Therapy. Archived from the original on 2014-08-06. Retrieved 2014-06-25.

Journals:

• "Pharmacogenomics". Future Medicine Ltd.
• "Pharmacogenetics and Genomics". Lippincott Williams & Wilkins. ISSN 1744-6872.
• "The Pharmacogenomics Journal". The Pharmacogenomics Journal. Nature Publishing Group. ISSN 1470-269X.