Mypgx Abstract Booklet

MyPGx® Abstract booklet July 2018

Version number: 003

Content

I. General information abstracts – Pharmacogenetics (PGx), single nucleotide polymorphisms (SNPs) and adverse drug reactions (ADRs) 2

II. Psychiatry - MyPSY 10

III. Rheumatology - MyRHUMA 14

IV. Neuology – MyNEURO 16

V. Oncology – MyONCO 18

VI. Cardiology– MyCARDIO 21

VII. APPENDIX 1: U.S.Food & Drug administration (FDA) PGx Biomarker in drug labelling 26

VIII. APPENDIX 2: Genetic biomarkers associated with inter-individual differences in drug pharmacokinetic or pharmacodynamics parameters 42

I. General information abstracts – Pharmacogenetics (PGx), single nucleotide polymorphisms (SNPs) and adverse drug reactions (ADRs)

A Survey on Polypharmacy and Use of Inappropriate Medications

Rambhade, S., Chakarborty, A., Shrivastava, A., Patil, U. K., & Rambhade, A. (2012). A survey on polypharmacy and use of inappropriate medications. Toxicology international, 19(1), 68.

In the past, polypharmacy was referred to the mixing of many drugs in one prescription. Today polypharmacy implies to the prescription of too many medications for an individual patient, with an associated higher risk of adverse drug reactions (ADRs) and interactions. Situations certainly exist where the combination therapy or polytherapy is the used for single disease condition. Polypharmacy is a problem of substantial importance, in terms of both direct medication costs and indirect medication costs resulting from drug-related morbidity. Polypharmacy increases the risk of side effects and interactions. Moreover it is a preventable problem. A retrospective study was carried out at Bhopal district (Capital of Madhya Pradesh, India) in the year of September-November 2009 by collecting prescriptions of consultants at various levels of health care. The tendency of polypharmacy was studied and analyzed under the various heads in the survey. Available data suggests that polypharmacy is a widespread problem, and physician, clinical pharmacists and patients are all responsible. These risks can be minimized through identifying the prevalence of this potential problem in a high-risk population and by increasing awareness among patients and healthcare professionals. Physicians and clinical pharmacists have the potential to c ombating this problem through a variety of interventions such as reducing the number of medications taken, reducing the number of doses taken, increasing patient adherence, preventing ADRs, improving patient quality of life and decreasing facility and drug costs.

Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients

Pirmohamed, M., James, S., Meakin, S., Green, C., Scott, A. K., Walley, T. J., ... & Breckenridge, A. M. (2004). Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. Bmj, 329(7456), 15-19.

Objective: To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. Design: Prospective observational study. Setting: Two large general hospitals in Merseyside, England. Participants: 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. Main outcome measures: Prevalence of admissions due to an ADR, length of stay, avoid ability, and outcome.

Results: There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is 466m pounds sterling (706m Euros, 847m dollars). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding.

Conclusion: The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs. © 2018 SYNLAB International GmbH. All rights reserved. MyPGx® is a registered trade mark of SYNLAB International GmbH. 2

Clinical and economic burden of adverse drug reactions

Sultana, J., Cutroneo, P., & Trifirò, G. (2013). Clinical and economic burden of adverse drug reactions. Journal of pharmacology & pharmacotherapeutics, 4(Suppl1), S73.

Adverse drug reactions (ADRs) are unwanted drug effects that have considerable economic as well as clinical costs as they often lead to hospital admission, prolongation of hospital stay and emergency department visits. Randomized controlled trials (RCTs) are the main premarketing methods used to detect and quantify ADRs but these have several limitations, such as limited study sample size and limited heterogeneity due to the exclusion of the frailest patients. In addition, ADRs due to inappropriate medication use occur often in the real world of clinical practice but not in RCTs. Postmarketing drug safety monitoring through pharmacovigilance activities, including mining of spontaneous reporting and carrying out observational prospective cohort or retrospective database studies, allow longer follow-up periods of patients with a much wider range of characteristics, providing valuable means for ADR detection, quantification and where possible reduction, reducing healthcare costs in the process.

Overall, pharmacovigilance is aimed at identifying drug safety signals as early as possible, thus minimizing potential clinical and economic consequences of ADRs. The goal of this review is to explore the epidemiology and the costs of ADRs in routine care.

Clinical impact of pharmacogenetic profiling with a clinical decision support tool in polypharmacy home health patients: A prospective pilot randomized controlled trial

Elliott, L. S., Henderson, J. C., Neradilek, M. B., Moyer, N. A., Ashcraft, K. C., & Thirumaran, R. K. (2017). Clinical impact of pharmacogenetic profiling with a clinical decision support tool in polypharmacy home health patients: A prospective pilot randomized controlled trial. PloS one, 12(2), e0170905

Background: In polypharmacy patients under home health management, pharmacogenetic testing coupled with guidance from a clinical decision support tool (CDST) on reducing drug, gene, and cumulative interaction risk may provide valuable insights in prescription drug treatment, reducing re-hospitalization and emergency department (ED) visits. We assessed the clinical impact of pharmacogenetic profiling integrating binary and cumulative drug and gene interaction warnings on home health polypharmacy patients.

Methods and findings: This prospective, open-label, randomized controlled trial was conducted at one hospital- based home health agency between February 2015 and February 2016. Recruitment came from patient referrals to home health at hospital discharge. Eligible patients were aged 50 years and older and taking or initiating treatment with medications with potential or significant drug-gene-based interactions. Subjects (n = 110) were randomized to pharmacogenetic profiling (n = 57). The study pharmacist reviewed drug-drug, drug-gene, and cumulative drug and/or gene interactions using the YouScript® CDST to provide drug therapy recommendations to clinicians. The control group (n = 53) received treatment as usual including pharmacist guided medication management using a standard drug information resource. The primary outcome measure was the number of re-hospitalizations and ED visits at 30 and 60 days after discharge from the hospital.

The mean number of re-hospitalizations per patient in the tested vs. untested group was 0.25 vs. 0.38 at 30 days (relative risk (RR), 0.65; 95% confidence interval (CI), 0.32–1.28; P = 0.21) and 0.33 vs. 0.70 at 60 days following enrollment (RR, 0.48; 95% CI, 0.27–0.82; P = 0.007). The mean number of ED visits per patient in the tested vs.

untested group was 0.25 vs. 0.40 at 30 days (RR, 0.62; 95% CI, 0.31–1.21; P = 0.16) and 0.39 vs. 0.66 at 60 days (RR, 0.58; 95% CI, 0.34–0.99; P = 0.045). Differences in composite outcomes at 60 days (exploratory endpoints) were also found. Of the total 124 drug therapy recommendations passed on to clinicians, 96 (77%) were followed. These findings should be verified with additional prospective confirmatory studies involving real-world applications in larger populations to broaden acceptance in routine clinical practice.

Conclusions: Pharmacogenetic testing of polypharmacy patients aged 50 and older, supported by an appropriate CDST, considerably reduced re-hospitalizations and ED visits at 60 days following enrollment resulting in potential health resource utilization savings and improved healthcare.

Cost-Effectiveness of Pharmacogenomic and Pharmacogenetic Test-Guided Personalized Therapies: A Systematic Review of the Approved Active Substances for Personalized Medicine in Germany

Plöthner, M., Ribbentrop, D., Hartman, J. P., & Frank, M. (2016). Cost-effectiveness of pharmacogenomic and pharmacogenetic test-guided personalized therapies: a systematic review of the approved active substances for personalized medicine in Germany. Advances in therapy, 33(9), 1461-1480.

Background: The use of targeted therapies has recently increased. Pharmacogenetic tests are a useful tool to guide patient treatment and to test a response before administering medicines. Pharmacogenetic tests can predict potential drug resistance and may be used for determining genotype-based drug dosage. However, their cost-effectiveness as a diagnostic tool is often debatable. In Germany, 47 active ingredients are currently approved. A prior predictive test is required for 39 of these and is recommended for eight. The objective of this study was to review the cost - effectiveness (CE) of pharmacogenetic test-guided drug therapy and compare the application of drugs with and without prior genetic testing.

Methods: A systematic literature review was conducted to identify the CE and cost-utility of genetic tests. Studies from January 2000 until November 2015 were searched in 16 databases including Medline, Embase, and Cochrane. A quality assessment of the full-text publications was performed using the validated Quality of Health Economic Studies (QHES) instrument.

Results: In the majority of the included studies, the pharmacogenetic test-guided therapy represents a cost- effective/cost-saving treatment option. Only seven studies lacked a clear statement of CE or cost -savings, because of uncertainty, restriction to specific patient populations, or assumptions for comparative therapy. Moreover, the high quality of the available evidence was evaluated.

Conclusion: Pharmacogenetic testing constitutes an opportunity to improve the CE of pharmacotherapy. The CE of targeted therapies depends on various factors including costs, prevalence of biomarkers, and test sensitivity and specificity. To guarantee the CE comparability of stratified drug therapies, national and international standards for evaluation studies should be defined.

Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation

Zanger, U. M., & Schwab, M. (2013). Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology & therapeutics, 138(1), 103-141.

Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics and response. Of 57 putatively functional human CYPs only about a dozen enzymes, belonging to the CYP1, 2, and 3 families, are responsible for the biotransformation of most foreign substances including 70–80% of all drugs in clinical use. The highest expressed forms in liver are CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19 and 3A5 are less abundant and CYPs 2J2, 1A1, and 1B1 are mainly expressed extrahepatically. Expression of each CYP is influenced by a unique combination of mechanisms and factors including genetic polymorphisms, induction by xenobiotics, regulation by cytokines, hormones and during disease states, as well as sex, age, and others. Multiallelic genetic polymorphisms, which strongly depend on ethnicity, play a major role for the function of CYPs 2D6, 2C19, 2C9, 2B6, 3A5 and 2A6, and lead to distinct pharmacogenetic phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers. For these CYPs, the evidence for clinical significance regarding adverse drug reactions (ADRs), drug efficacy and dose requirement is rapidly growing. Polymorphisms in CYPs 1A1, 1A2, 2C8, 2E1, 2J2, and 3A4 are generally less predictive, but new data on CYP3A4 show that predictive variants exist and that additional variants in regulatory genes or in NADPH: cytochrome P450 oxidoreductase (POR) can have an influence. Here we review the recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s.

dbSNP—Database for Single Nucleotide Polymorphisms and Other Classes of Minor Genetic Variation

Sherry, S. T., Ward, M., & Sirotkin, K. (1999). dbSNP—database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome research, 9(8), 677-679.

A key aspect of research in genetics is associating sequence variations with heritable phenotypes. The most common variations are single nucleotide polymorphisms (SNPs), which occur approximately once every 500–1000 bases in a large sample of aligned human sequence. Because SNPs are expected to facilitate large-scale association genetics studies, there has recently been great interest in SNP discovery and detection. In collaboration with the National Human Genome Research Institute (NHGRI), the National Center for Biotechnology Information (NCBI) has established the dbSNP database (http://www.ncbi.nlm.nih.gov/SNP) to serve as a central repository for molecular variation. Designed to serve as a general catalog of molecular variation to supplement GenBank (Benson et al. 1999) database submissions can include a broad range of molecular polymorphisms: single base nucleotide substitutions, short deletion and insertion polymorphisms, microsatellite markers, and polymorphic insertion elements such as retrotransposons.

Genetic Polymorphisms, Drug Metabolism and Drug Concentrations

Shenfield, G. M. (2004). Genetic polymorphisms, drug metabolism and drug concentrations. The Clinical Biochemist Reviews, 25(4), 203.

The interfaces between genetics and drug metabolism have recently been the subjects of intense research activity. Pharmacogenomics uses molecular biological techniques to study genes in relation to drug therapy for specific diseases in order to identify new treatments. Pharmacogenetics investigates the genetic basis for differences in individual responses to drugs with regard to their metabolism and transport in the body. A genetic polymorphism occurs if, within a population, a single gene responsible for producing a metabolising enzyme has a variant allele with the arbitrary frequency of 1%. For many such genes single nucleotide polymorphisms (SNP) exist and an allelic site may have more than one SNP. Genotype is the detailed gene structure of an individual whereas the more commonly measured phenotype is the outcome of metabolism of a drug in an individual. Since phenotype i s the result of interactions between genetic make-up and the environment it is not always concordant with genotype.

GENOMIC RESEARCH: WHAT ARE SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS)?

Lister Hill National Center for Biomedical Communications U.S. National Library of Medicine National Institutes of Health Department of Health & Human Services Published February 13, 2018. Genetics Home Reference - https://ghr.nlm.nih.gov/ Single nucleotide polymorphisms, frequently called SNPs (pronounced “snips”), are the most common type of genetic variation among people. Each SNP represents a difference in a single DNA building block, called a nucleotide. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA . SNPs occur normally throughout a person’s DNA. They occur once in every 300 nucleotides on average, which means there are roughly 10 million SNPs in the human genome. Most commonly, these variations are found in the DNA between genes. They can act as biological markers, helping scientists locate genes that are associated with disease. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function. Most SNPs have no effect on health or development. Some of these genetic differences, however, have proven to be very important in the study of human health. Researchers have found SNPs that may help predict an individual’s response to certain drugs, susceptibility to environmental factors such as toxins, and risk of developing particular diseases. SNPs can also be used to track the inheritance of disease genes within families. Future studies will work to identify SNPs associated with complex diseases such as heart disease, diabetes , and cancer.

Hospital Admissions Associated with Adverse Drug Reactions: A Systematic Review of Prospective Observational Studies

Kongkaew, C., Noyce, P. R., & Ashcroft, D. M. (2008). Hospital admissions associated with adverse drug reactions: a systematic review of prospective observational studies. Annals of Pharmacotherapy, 42(7-8), 1017-1025.

Objective: To determine the prevalence of hospital admissions associated with ADRs and examine differences in prevalence rates between population groups and methods of ADR detection.

Data Sources: Studies were identified through electronic searches of Cumulative Index to Nursing and Allied Hearth Literature. EMBASE, and MEDLINE to August 2007. There were no language restrictions.

Study Selection and Data Extraction: A systematic review was conducted of prospective observational studies that used the World Health Organization ADR definition. Subgroup analysis examined the influence of patient age groups and methods of ADR detection on reported ADR admission rates. All statistical analyses were performed using STATA v 9.0.

Data Synthesis: Twenty-five studies were identified including 106, 586 patients who were hospitalized; 2143 of these patients had experienced ADRs. The prevalence rates of ADRs ranged from 0.16% to 15.7%, with an overall median of 5.3% (interquartile range [IQR] 2.7–9.0%). Median ADR prevalence rates varied between age groups: for children, the ADR admission rate was 4.1% (IQR 0.16–5.3%), while the corresponding rates for adults and elderly patients were 6.3% (IQR 3.9–9.0%) and 10.7% (IQR 9.6–13.3%), respectively. ADR rates also varied depending on the methods of ADR detection employed in the different studies. Studies that employed multiple ADR detection methods, such as medical record review and patient interview, reported higher ADR admission rates compared with studies that used medical record review alone. Antiinfective drugs were most often associated with ADR admissions in children; cardiovascular drugs were most often associated with ADR admissions in adults and elderly patients.

Conclusions: Approximately 5.3% of hospital admissions were associated with ADRs. Higher rates were found in elderly patients who are likely to be receiving multiple medications for long-term illnesses. The methods used to detect ADRs are also likely to explain much of the variation in the reported ADR prevalence rates between different studies.

Initial assessment of the benefits of implementing pharmacogenetics into the medical management of patients in a long-term care facility

Saldivar, J. S., Taylor, D., Sugarman, E. A., Cullors, A., Garces, J. A., Oades, K., & Centeno, J. (2016). Initial assessment of the benefits of implementing pharmacogenetics into the medical management of patients in a long- term care facility. Pharmacogenomics and personalized medicine, 9, 1.

The health care costs associated with prescription drugs are enormous, particularly in patients with polypharmacy (taking more than five prescription medications), and they continue to grow annually. The evolution of pharmacogenetics has provided clinicians with a valuable tool that allows for a smarter, more fine-tuned approach to treating patients for a number of clinical conditions. Applying a pharmacogenetics approach to the medical management of patients can provide a significant improvement to their care, result in cost savings by reducing the use of ineffective drugs, and decrease overall health care utilization. AltheaDx has begun a study to look at the benefits associated with incorporating pharmacogenetics into the medical management of patients who are on five or more medications. Applying pharmacogenetic guided PharmD recommendations across this patient population resulted in the elimination and/or replacement of one to three drugs, for 50% of the polypharmacy patient population tested, and an estimated US$621 in annual savings per patient. The initial assessment of this study shows that there is a clear opportunity for concrete health care savings solely from prescription drug management when incorporating pharmacogenetic testing.

Pharmacogenetics. Current status – facts and fiction Cascorbi, Ingolf. (2017). Pharmakogenetik: Aktueller Stand – Fakten und Fiktionen. medizinische Genetik. 10.1007/s11825-017-0146-2.

Interindividual differences in drugs with regard to efficacy and safety are a significant health care problem and genetic variation contributes to this. The aims of this study were to give an overview of the current knowledge on pharmacogenetics and regulatory aspects, and to discuss questions on the problems of implementation in the clinic by reviewing the recent literature. The guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC) are currently the scientifically most advanced starting point for pharmacogenetics-based selection and dosing of selected drugs. On a national level, the guidelines of the gene diagnostics commission provide a framework of which classes should be considered in the classification of the significance of hereditary variants in relation to their efficacy and tolerability. Although there is already evidence for certain gene–drug pairs with regard to their clinical and economic utility, there is a need to prove the success of the clinical application of a large number of gene–drug pairs through prospective or preemptive genotyping-based studies. Such studies are currently ongoing in large research consortia, in Europe and especially in North America.

Pharmacogenetics-based personalized therapy: Levels of evidence and recommendations from the French Network of Pharmacogenetics (RNPGx).

Picard, N., Boyer, J. C., Etienne-Grimaldi, M. C., Barin-Le Guellec, C., Thomas, F., & Loriot, M. A. (2017). Pharmacogenetics-based personalized therapy: Levels of evidence and recommendations from the French Network of Pharmacogenetics (RNPGx). Therapie, 72(2), 185-192.

More than 50 laboratories offer pharmacogenetic testing in France. These tests are restricted to a limited number of indications: prevention of serious adverse drug reactions; choice of most appropriate therapeutic option; dose adjustment for a specific drug. A very small proportion of these tests are mentioned in drug information labeling and the data provided (if any) are generally insufficient to ascertain whether a test is required and if it is useful. Thi s article discusses the rationale for evaluating the performance and clinical usefulness of pharmacogenetics and provides, on behalf of the French national network of pharmacogenetics (RNPGx), three levels of recommendation for testing: essential, advisable, and possibly helpful.

Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine.

Ahmed, S., Zhou, Z., Zhou, J., & Chen, S. Q. (2016). Pharmacogenomics of drug metabolizing enzymes and transporters: relevance to precision medicine. Genomics, proteomics & bioinformatics, 14(5), 298-313.

The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual's particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in

key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.

Pharmacogenomics: The Right Drug to the Right Person

Aneesh, T. P., Sekhar, S., Jose, A., Chandran, L., & Zachariah, S. M. (2009). Pharmacogenomics: the right drug to the right person. Journal of clinical medicine research, 1(4), 191.

Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. It aims to develop rational means to optimize drug therapy, with respect to the patients genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of personalized medicine, in which drugs and drug combinations are optimized for each individual's unique genetic makeup. Pharmacogenomics is the whole genome application of pharmacogenetics, which examines the single gene interactions with drugs.

II. Psychiatry - MyPSY

Clinical Impact of Pharmacogenetic-Guided Treatment for Patients Exhibiting Neuropsychiatric Disorders: A Randomized Controlled Trial.

Olson, M. C., Maciel, A., Gariepy, J. F., Cullors, A., Saldivar, J. S., Taylor, D., ... & Vaishnavi, S. (2017). Clinical Impact of Pharmacogenetic-Guided Treatment for Patients Exhibiting Neuropsychiatric Disorders: A Randomized Controlled Trial. The primary care companion for CNS disorders, 19(2).

Pharmacogenetic testing holds promise as a personalized medicine tool by permitting individualization of pharmacotherapy in accordance with genes influencing therapeutic response, side effects, and adverse events. The authors evaluated the effect on outcomes for patients diagnosed with neuropsychiatric disorders of pharmacogenetics (PGx)-guided treatment compared to usual standard of care. Conclusions: Pharmacogenetics testing may facilitate psychiatric drug therapy with greater tolerability and similar efficacy compared to standard of care.

Codeine Therapy and CYP2D6 Genotype

Dean, L. (2017). Codeine therapy and CYP2D6 genotype.

Codeine is used to relieve mild to moderately severe pain, and it belongs to the drug class of opioid analgesics.

The hepatic CYP2D6 enzyme metabolizes a quarter of all prescribed drugs, including codeine. CYP2D6 converts codeine in to its active metabolite, morphine, which provides its analgesic effect. However, pain relief may be inadequate in individuals who carry two inactive copies of CYP2D6 (“poor metabolizers”), because of reduced morphine levels. In contrast, individuals who carry more than two normal function copies of the CYP2D6 gene (“ultrarapid metabolizers”) are able to metabolize codeine to morphine more rapidly and more completely. As a result, even with normal doses of codeine, these individuals may experience the symptoms of morphine overdose, which include extreme sleepiness, confusion, and shallow breathing. Nursing mothers may also produce breast milk containing higher than expected levels of morphine that can lead to severe adverse events in their infants (1).

The FDA drug label for codeine states that even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose. The label also contains a boxed warning, which states that respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that for a patient identified as a CYP2D6 ultrarapid metabolizer, another analgesic should be used to avoid the risk of severe toxicity with a “normal” dose of codeine. CPIC also recommends avoiding codeine in patients identified as CYP2D6 poor metabolizers due to the possibility of lack of effect.

Intuitive pharmacogenetic dosing of risperidone according to CYP2D6 phenotype extrapolated from genotype in a cohort of first episode psychosis patients.

Mas, S., Gassó, P., Torra, M., Bioque, M., Lobo, A., González-Pinto, A., ... & Rodriguez-Jimenez, R. (2017). Intuitive pharmacogenetic dosing of risperidone according to CYP2D6 phenotype extrapolated from genotype in a cohort of first episode psychosis patients. European Neuropsychopharmacology, 27(7), 647-656.

Risperidone (R) is the most prescribed antipsychotic drug for patients with a first episode of psychosis (FEP). In a naturalistic cohort of chronic psychiatric inpatients, we demonstrated that clinicians adjust R dosage by CYP2D6 activity, despite being blinded to the genotype, which we described as an "intuitive pharmacogenetic" process. The aim of the present study is to replicate our previous findings of intuitive pharmacogenetic in a cohort of FEP patients using CYP2D6 phenotype extrapolated from genotypes. 70 FEP patients, under baseline treatment with R monotherapy were genotyped using the iPLEX® ADME PGx multiplex panel and TaqMan® Genotyping and Copy Number Assays. Plasma concentrations of R and its metabolite, 9-hydroxyrisperidone (9-OH), were determined. The predictive properties of those variables associated with R dosage were tested using a multiple linear regression model as well as regression trees. Significant differences in the mean daily dosage of R among CYP2D6 phenotypes were observed (Kruskal-Wallis test p=0.02): PM (4.00±2.3mg/mL), IM (4.56±2.44), EM (6.22±4.0mg/day) and UM (10.20±4.91mg/day). However, non-significant differences were observed in the R/9-OH ratio or in the Concentration/Dose ratio. Regression tree provided better estimations of R dosage than the multiple linear regression model (MAE=0.958 and R2=0.871). We confirm the "intuitive pharmacogenetic" dosing of R according to the CYP2D6 phenotype in a FEP cohort. The results presented provides a rationale for the clinical use of CYP2D6 genotyping in personalized medicine.

Pharmacogenomics of antipsychotics efficacy for schizophrenia

Cacabelos, R., Hashimoto, R., & Takeda, M. (2011). Pharmacogenomics of antipsychotics efficacy for schizophrenia. Psychiatry and clinical neurosciences, 65(1), 3-19.

Central nervous system disorders are the third greatest health problem in developed countries, and schizophrenia represents some of the most disabling ailments in young individuals. There is an abuse and/or misuse of antipsychotics, and recent advances in pharmacogenomics pose new challenges for the clinical management of this complex disorder. Schizophrenia is a multi-factorial/polygenic complex disorder in which hundreds of different genes are potentially involved, leading to the phenotypic expression of the disease in conjunction with epigenetic and environmental phenomena. Consequently, structural and functional genomic changes induce proteomic and metabolomic defects associated with the disease phenotype.

Disease-related genomic profiles and genetic variants in genes involved in drug metabolism are responsible for drug efficacy and safety. About 20% of Caucasians are defective in CYP2D6 enzymes, which participate in the metabolism of 25–30% of central nervous system drugs. Approximately 40% of antipsychotics are substrates of CYP2D6 enzymes, 23% are substrates of CYP3A4, and 18% are substrates of CYP1A2. In order to achieve a mature discipline of pharmacogenomics of schizophrenia it would be effective to accelerate: (i) the education of physicians and the public in the use of genomic screening in daily clinical practice; (ii) the standardization of genetic testing for major categories of drugs; (iii) the validation of pharmacogenomic procedures according to drug category and pathology; (iv) the regulation of ethical, social, and economic issues; and (v) the incorporation of pharmacogenomic procedures of drugs in development and drugs on the market in order to optimize therapeutics.

Treatment-resistant depression: therapeutic trends, challenges, and future directions

Al-Harbi, K. S. (2012). Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient preference and adherence, 6, 369.

Background: Patients with major depression respond to antidepressant treatment, but 10%–30% of them do not improve or show a partial response coupled with functional impairment, poor quality of life, suicide ideation and attempts, self-injurious behavior, and a high relapse rate. The aim of this paper is to review the therapeutic options for treating resistant major depressive disorder, as well as evaluating further therapeutic options.

Methods: In addition to Google Scholar and Quertle searches, a PubMed search using key words was conducted, and relevant articles published in English peer-reviewed journals (1990–2011) were retrieved. Only those papers that directly addressed treatment options for treatment-resistant depression were retained for extensive review.

Results: Treatment-resistant depression, a complex clinical problem caused by multiple risk factors, is targeted by integrated therapeutic strategies, which include optimization of medications, a combination of antidepressants, switching of antidepressants, and augmentation with non-antidepressants, psychosocial and cultural therapies, and somatic therapies including electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation, transcranial direct current stimulation, and vagus nerve stimulation. As a corollary, more than a third of patients with treatment-resistant depression tend to achieve remission and the rest continue to suffer from residual symptoms. The latter group of patients needs further study to identify the most effective therapeutic modalities. Newer biomarker-based antidepressants and other drugs, together with non-drug strategies, are on the horizon to address further the multiple complex issues of treatment-resistant depression.

Conclusion: Treatment-resistant depression continues to challenge mental health care providers , and further relevant research involving newer drugs is warranted to improve the quality of life of patients with the disorder.

World health report: Mental disorders affect one in four people. Treatment available but not being used http://www.who.int/whr/2001/media_centre/press_release/en/

Geneva, 4 October— One in four people in the world will be affected by mental or neurological disorders at some point in their lives. Around 450 million people currently suffer from such conditions, placing mental disorders among the leading causes of ill-health and disability worldwide. Up to 60% of people with depression can recover with a proper combination of antidepressant drugs and psychotherapy.

Treatments are available, but nearly two-thirds of people with a known mental disorder never seek help from a health professional. Stigma, discrimination and neglect prevent care and treatment from reaching people with mental disorders, says the World Health Organization (WHO). Where there is neglect, there is little or no understanding. Where there is no understanding, there is neglect.

III. Rheumatology - MyRHUMA

Codeine Therapy and CYP2D6 Genotype

Dean, L. (2017). Codeine therapy and CYP2D6 genotype.

Codeine is used to relieve mild to moderately severe pain, and it belongs to the drug class of opioid analgesics.

In contrast, individuals who carry more than two normal function copies of the CYP2D6 gene (“ultrarapid metabolizers”) are able to metabolize codeine to morphine more rapidly and more completely. As a result, even with normal doses of codeine, these individuals may experience the symptoms of morphine overdose, which include extreme sleepiness, confusion, and shallow breathing. Nursing mothers may also produce breast milk containing higher than expected levels of morphine that can lead to severe adverse events in their infants.

Pharmacogenetics of analgesic drugs

Cregg, R., Russo, G., Gubbay, A., Branford, R., & Sato, H. (2013). Pharmacogenetics of analgesic drugs. British journal of pain, 7(4), 189-208.

Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined.

• Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications.

• While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype – phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor).

• Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future.

• This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain.

IV. Neuology – MyNEURO

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos, R. (2017). Parkinson’s disease: from pathogenesis to pharmacogenomics. International journal of molecular sciences, 18(3), 551.

Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, persona lized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

Pharmacogenomics in Alzheimer's disease.

Cacabelos, R. (2008). Pharmacogenomics in Alzheimer's disease. In Pharmacogenomics in Drug Discovery and Development (pp. 213-357). Humana Press.

Pharmacological treatment in Alzheimer's disease (AD) accounts for 10-20% of direct costs, and fewer than 20% of AD patients are moderate responders to conventional drugs (donepezil, rivastigmine, galantamine, memantine), with doubtful cost-effectiveness. Both AD pathogenesis and drug metabolism are genetically regulated complex traits in which hundreds of genes cooperatively participate. Structural genomics studies demonstrated that more than 200 genes might be involved in AD pathogenesis regulating dysfunctional genetic networks leading to premature neuronal death. The AD population exhibits a higher genetic variation rate than the control population, with absolute and relative genetic variations of 40-60% and 0.85-1.89%, respectively. AD patients also differ in their genomic architecture from patients with other forms of dementia. Functional genomics studies in AD revealed that age of onset, brain atrophy, cerebrovascular hemodynamics, brain bioelectrical activity, cognitive decline, apoptosis, immune function, lipid metabolism dyshomeostasis, and amyloid deposition are associated with AD-related genes. Pioneering pharmacogenomics studies also demonstrated that the therapeutic response in AD is genotype-specific, with apolipoprotein E (APOE) 4/4 carriers the worst responders to conventional treatments. About 10-20% of Caucasians are carriers of defective cytochrome P450 (CYP) 2D6 polymorphic variants that alter the metabolism

and effects of AD drugs and many psychotropic agents currently administered to patients with dementia. There is a moderate accumulation of AD-related genetic variants of risk in CYP2D6 poor metabolizers (PMs) and ultrarapid metabolizers (UMs), who are the worst responders to conventional drugs. The association of the APOE -4 allele with specific genetic variants of other genes (e.g., CYP2D6, angiotensin-converting enzyme [ACE]) negatively modulates the therapeutic response to multifactorial treatments affecting cognition, mood, and behavior. Pharmacogenetic and pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenetic/pharmacogenomic protocols to AD research and clinical practice can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety.

Pharmacogenomics of Alzheimer's disease: novel therapeutic strategies for drug development.

Cacabelos, R., Cacabelos, P., Torrellas, C., Tellado, I., & Carril, J. C. (2014). Pharmacogenomics of Alzheimer’s disease: Novel therapeutic strategies for drug development. In Pharmacogenomics in Drug Discovery and Development (pp. 323-556). Humana Press, New York, NY.

Alzheimer's disease (AD) is a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis, and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cos t-effective. As a complex disorder, AD is a polygenic and multifactorial clinical entity in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions, lead to amyloid deposition, neurofibrillary tangle formation, and premature neuronal death, the major neuropathological hallmarks of AD. Future perspectives for the global management of AD predict that genomics and proteomics may help in the search for reliable biomarkers. In practical terms, the therapeutic response to conventional drugs (cholinesterase inhibitors, multifactorial strategies) is genotype-specific. Genomic factors potentially involved in AD pharmacogenomics include at least five categories of gene clusters: (1) genes associated with disease pathogenesis; (2) genes associated with the mechanism of action of drugs; (3) genes associated with drug metabolism (phase I and II reactions); (4) genes associated with drug transporters; and (5) pleiotropic genes involved in multifaceted cascades and metabolic reactions. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.

Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials.

Tortelli, R., Seripa, D., Panza, F., Solfrizzi, V., & Logroscino, G. (2016). Pharmacogenetics in Neurodegenerati ve Diseases: Implications for Clinical Trials. In The Right Therapy for Neurological Disorders (Vol. 39, pp. 124-135). Karger Publishers.

Background: Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases.

Summary: Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes

influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted.

Key messages: The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification.

V. Oncology – MyONCO

Precision medicine and pharmacogenetics: what does oncology have that addiction medicine does not?

Kranzler, H. R., Smith, R. V., Schnoll, R., Moustafa, A., & Greenstreet‐Akman, E. (2017). Precision medicine and pharmacogenetics: what does oncology have that addiction medicine does not?. Addiction, 112(12), 2086-2094.

Background: Precision, personalized or stratified medicine, which promises to deliver the right treatment to the right patient, is a topic of international interest in both the lay press and the scientific literature. A key aspect of precision medicine is the identification of biomarkers that predict the response to medications (i.e. pharmacogenetics). We examined why, despite the great strides that have been made in biomarker identification in many areas of medicine, only in oncology has there been substantial progress in their clinical implementation. We also considered why progress in this effort has lagged in addiction medicine.

Methods: We compared the development of pharmacogenetic biomarkers in oncology, cardiovascular medicine (where developments are also promising) and addictive disorders.

Results: The first major reason for the success of oncologic pharmacogenetics is ready access to tumor tissue, which allows in-vitro testing and insights into cancer biology. The second major reason is funding, with cancer research receiving, by far, the largest allocation by the National Institutes of Health (NIH) during the past two decades. The second largest allocation of research funding has gone to cardiovascular disease research. Addictions research received a much smaller NIH funding allocation, despite the major impact that tobacco use, alcohol consumption and illicit drug use have on the public health and healthcare costs.

Conclusions: Greater support for research on the personalized treatment of addictive disorders can be expected to yield disproportionately large benefits to the public health and substantial reductions in healthcare costs.

Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity.

Loganayagam, A., Hernandez, M. A., Corrigan, A., Fairbanks, L., Lewis, C. M., Harper, P., . .. & Marinaki, A. M. (2013). Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. British journal of cancer, 108(12), 2505.

Background: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity.

Methods: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models.

Results: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻⁶, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.- 451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively).

Conclusion: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.

Irinotecan pharmacogenomics

Marsh, S., & Hoskins, J. M. (2010). Irinotecan pharmacogenomics. Pharmacogenomics, 11(7), 1003-1010.

Irinotecan is a camptothecin analog used as an anticancer drug. Severe, potentially life-threatening toxicities can occur from irinotecan treatment. Although multiple genes may play a role in irinotecan activity, the majority of evidence to date suggests that variation in expression of UGT1A1 caused by a common promoter polymorphism (UGT1A1*28) is strongly associated with toxicity; however, this link is dose dependent. Variations in other pharmacokinetic genes, particularly the transporter ABCC2, also contribute to irinotecan toxicity. In addition, recent studies have shown that pharmacodynamic genes such as TDP1 and XRCC1 can also play a role in both toxicity and response.

Tamoxifen Therapy and CYP2D6 Genotype

Dean, L. (2016). Tamoxifen therapy and CYP2D6 genotype.

Tamoxifen is a selective estrogen receptor modulator (SERM) which is used in the treatment and prevention of breast cancer.

The CYP2D6 enzyme metabolizes a quarter of all prescribed drugs, and is one of the main enzymes responsible for converting tamoxifen into its major active metabolite, endofixen. Variants in the CYP2D6 allele may lead to reduced

(“intermediate metabolizer”) or absent (“poor metabolizer”) enzyme activity. Individuals who carry these variant alleles may have reduced plasma concentrations of endoxifen and benefit less from tamoxifen therapy.

At this time, the FDA-approved drug label for tamoxifen does not discuss genetic testing for CYP2D6. The National Comprehensive Cancer Network (NCCN) does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy, and this recommendation is consistent with the 2010 guidelines from the American Society of Clinical Oncology (ASCO).

In contrast, the Dutch Pharmacogenetics Working Group has made recommendations for tamoxifen therapy based on CYP2D6 genotypes. For both poor and intermediate metabolizers, their recommendation is to consider using aromatase inhibitors for postmenopausal women due to an increased risk for relapse of breast cancer with tamoxifen. They also recommend that intermediate metabolizers avoid the concomitant use of CYP2D6 inhibitors .

Phenotype Genotype Therapeutic recommendation for tamoxifen

Ultrarapid More than two copies of functional alleles None metabolizer

Intermediate One active allele and one inactive allele, or Increased risk for relapse of breast cancer. Avoid metabolizer two decreased activity alleles, or one concomitant use of CYP2D6 inhibitors. Consider decreased activity allele and one inactive aromatase inhibitor for postmenopausal women allele

Poor Two inactive alleles Increased risk for relapse of breast cancer. Consider metabolizer aromatase inhibitor for postmenopausal women The strength of the tamoxifen therapeutic recommendations scored a maximum of 4/4 (the highest quality of evidence). Table is adapted from Swen J.J., Nijenhuis M., de Boer A., Grandia L. et al. Pharmacogenetics: from bench to byte - an update of guidelines. Clinical pharmacology and therapeutics. 2011;89(5):662–73 (4).

VI. Cardiology– MyCARDIO

Adherence to Cardiovascular Medications: Lessons Learned and Future Directions

Kronish, I. M., & Ye, S. (2013). Adherence to cardiovascular medications: lessons learned and future directions. Progress in cardiovascular diseases, 55(6), 590-600.

Approximately 50% of patients with cardiovascular disease and/or its major risk factors have poor adherence to their prescribed medications. Finding novel methods to help patients improve their adherence to existing evidence-base d cardiovascular drug therapies has enormous potential to improve health outcomes while potentially reducing health care costs. The goal of this report is to provide a review of the current understanding of adherence to cardiovascular medications from the point of view of prescribing clinicians and cardiovascular researchers. Key topics addressed include: 1) definitions of medication adherence; 2) prevalence and impact of non-adherence; 3) methods for assessing medication adherence; 4) reasons for poor adherence; and 5) approaches to improving adherence to cardiovascular medications. For each of these topics, the report seeks to identify important gaps in knowledge and opportunities for advancing the field of cardiovascular adherence research.

Cardiovascular diseases (CVDs) - World Health Organization

World Health Organization. (2014). http://www. who. int/mediacentre/factsheets/fs340/en. url> http://www. who. int/mediacentre/factsheets/fs241/en/

Cardiovascular diseases (CVDs) are disorders of the heart and blood vessels and include coronary heart disease, cerebrovascular disease, rheumatic heart disease and other conditions. More than 17 million people die annually from cardiovascular disease (CVD). Four out of five CVD deaths are due to heart attacks and strokes. Individuals at risk of CVD may demonstrate raised blood pressure, glucose, and lipids as well as overweight and obesity. These can all be easily measured in primary care facilities. Identifying those at highest risk of CVDs and ensuring they receive appropriate treatment can prevent premature deaths. Access to essential NCD medicines and basic health technologies in all primary health care facilities is essential to ensure that those in need receive treatment and counselling.

Chapter Thirteen - Pharmacogenetics in Cardiovascular Medicine

Weeke, P. E. (2018). Pharmacogenetics in Cardiovascular Medicine. Advances in Pharmacology, 83, 333-360.

Considerable interindividual variability in response to cardiovascular pharmacotherapy exists with drug responses varying from being efficacious to inadequate to induce severe adverse events. Fueled by advancements and multidisciplinary collaboration across disciplines such as genetics, bioinformatics, and basic research, the vision of personalized medicine, rather than a one-size-fits-all approach, may be within reach. Pharmacogenetics offers the potential to optimize the benefit–risk profile of drugs by tailoring diagnostic and treatment strategies according to the individual patient. To date, a multitude of studies has tried to delineate the effects of gene–drug interactions for drugs commonly used to treat cardiovascular-related disease. The focus of this review is on how genetic variability may modify drug responsiveness and patient outcomes following therapy with commonly used cardiovascular drugs

including clopidogrel, warfarin, statins, and β-blockers. Also included are examples of how genetic studies can be used to guide drug discovery and examples of how genetic information may be deployed in clinical decision making.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Pharmacogenetics- guided Warfarin Dosing: 2016 Update

Johnson, J. A., Caudle, K. E., Gong, L., Whirl‐Carrillo, M., Stein, C. M., Scott, S. A., ... & Anderson, J. L. (2017). Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics ‐guided warfarin dosing: 2017 update. Clinical Pharmacology & Therapeutics, 102(3), 397-404.

DRUG: WARFARIN

Background: Warfarin is administered as a racemic mixture of R- and S- stereoisomers. S-warfarin is 3-5 times more potent as a vitamin K antagonist than R-warfarin (2). The stereoisomers are extensively metabolized by different hepatic microsomal enzymes. S-warfarin is metabolized predominantly to 7- and 6- hydroxyl metabolites via CYP2C9 (Figure 1, main manuscript), whereas R-warfarin is mainly metabolized via CYP3A4 with involvement of CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18 and CYP2C19 (3-6). Warfarin exerts its anticoagulant effect through inhibition of its molecular target Vitamin K epoxide reductase complex (VKORC1) (7). VKORC1 catalyzes the conversion of oxidized Vitamin K to reduced Vitamin K with the help of microsomal epoxide hydrolas e (EPHX1). Warfarin blocks this reaction, which leads to decreased availability of the reduced Vitamin K that serves as a cofactor for gamma-glutamyl carboxylase (GGCX), and blocks the formation of functionally active clotting factors, leading to reduced coagulation (8-11).

Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design

Van Schie, R. M., Wadelius, M., Kamali, F., Daly, A. K., Manolopoulos, V. G., De Boer, A., ... & Briz, M. (2009). Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU- PACT) trial design. Pharmacogenomics, 10(10), 1687-1695.

The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.

Pharmacogenetics and Cardiovascular Disease—Implications for Personalized Medicine

Johnson, J. A., & Cavallari, L. H. (2013). Pharmacogenetics and cardiovascular disease—implications for personalized medicine. Pharmacological reviews, 65(3), 987-1009.

Abstract——The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients. There are many challenges in moving from research data to translation to practice; we discuss some of these barriers and the approaches some health systems are taking to overcome them. The body of literature that has led to the clinical implementation of CYP2C19 genotyping for clopidogrel, VKORC1, CYP2C9; and CYP4F2 for warfarin; and SLCO1B1 for statins is comprehensively described. We also provide clarity for other genes that have been extensively studied relative to these drugs, but for which the data are conflicting. Finally, we comment briefly on pharmacogenetics of other cardiovascular drugs and highlight b-blockers as the drug class with strong data that has not yet seen clinical implementation. It is anticipated that genetic information will increasingly be available on patients, and it is important to identify those examples where the evidence is sufficiently robust and predictive to use genetic information to guide clinical decisions. The reviewherein provides several examples of the accumulation of evidence and eventual clinical translation in cardiovascular pharmacogenetics.

Pharmacogenetics in Cardiovascular Medicine

Tuteja, S., & Limdi, N. (2016). Pharmacogenetics in Cardiovascular Medicine. Current genetic medicine reports, 4(3), 119-129.

Purpose of review—Pharmacogenetics is an important component of precision medicine. Even within the genomic era, several challenges lie ahead in the road towards clinical implementation of pharmacogenetics in the clinic. This © 2018 SYNLAB International GmbH. All rights reserved. MyPGx® is a registered trade mark of SYNLAB International GmbH. 23

review will summarize the current state of knowledge regarding pharmacogenetics of cardiovascular drugs, focusing on those with the most evidence supporting clinical implementation- clopidogrel, warfarin and simvastatin.

Recent findings—There is limited translation of pharmacogenetics into clinical practice primarily due to the absence of outcomes data from prospective, randomized, genotype-directed clinical trials. There are several ongoing randomized controlled trials that will provide some answers as to the clinical utility of genotype-directed strategies. Several academic medical centers have pushed towards clinical implementation where the clinical validity data are strong. Their experiences will inform operational requirements of a clinical pharmacogenetics testing including the timing of testing, incorporation of test results into the electronic health record, reimbursement and ethical issues.

Summary—Pharmacogenetics of clopidogrel, warfarin and simvastatin are three examples where pharmacogenetics testing may provide added clinical value. Continued accumulation of evidence surrounding clinical utility of pharmacogenetics markers is imperative as this will inform reimbursement policy and drive adoption of pharamcogenetics into routine care.

Statins, fibrates, nicotinic acid, cholesterol absorption inhibitors, anion-exchange resins, omega- 3 fatty acids: which drugs for which patients? Drexel, H. (2009). Statins, fibrates, nicotinic acid, cholesterol absorption inhibitors, anion‐exchange resins, omega‐3 fatty acids: which drugs for which patients?. Fundamental & clinical pharmacology, 23(6), 687-692.

ABSTRACT

Classes of lipid lowering drugs differ strongly with respect to the types of lipids or lipoproteins they predominantly affect. Statins inhibit the de-novo synthesis of cholesterol. Consequently, the liver produces less VLDL, and the serum concentration primarily of LDL cholesterol (but, to a lesser extent, also of triglycerides) is lowered. Further, statins somewhat increase HDL cholesterol. There is abundant evidence that statins lower the rate of cardiovascular events. Cardiovascular risk reduction is the better, the lower the LDL cholesterol values achieved with statin therapy are. Some evidence is available that anion exchange resins which also decrease LDL cholesterol decrease vascular risk, too. This is not the case for the ezetimibe, which strongly lowers LDL cholesterol: its potential to decrease vascular risk remains to be proven. In contrast evidence for cardiovascular risk reduction through the mainly triglyceride lowering fibrates as well as for niacin is available. Niacin is the most potent HDL increasing drug currently available and besides increasing HDL cholesterol efficaciously lowers triglycerides and LDL cholesterol. Large ongoing trials address the decisive question whether treatment with fibrates and niacin provides additional cardiovascular risk reduction when given in addition to statin treatment.

Warfarin Therapy and VKORC1 and CYP Genotype Dean, L. (2016). Warfarin therapy and the genotypes CYP2C9 and VKORC1.

Warfarin (brand name Coumadin) is an anticoagulant (blood thinner). Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors and is used in the prevention and treatment of various thrombotic disorders. Warfarin is a drug with narrow therapeutic index; thus, a small change in its plasma levels may result in concentration dependent adverse drug reactions or therapeutic failure. Therefore, the dose of warfarin must be tailored for each patient according to the patient’s response, measured as INR (International Normalized Ratio), and the condition being treated.

There is a wide inter-individual variability in the dose of warfarin required to achieve target anticoagulation, and the time it takes to reach target INR. Approximately half of this variability is known to be caused by clinical or lifestyle factors (e.g., a patient’s age, weight, BMI, gender, smoking status, existing conditions, and concomitant medications) and by genetic factors (known genetic factors include variants in the VKORC1, CYP2C9, CYP4F2 genes, and the rs12777823 variant in the CYP2C gene cluster on chromosome 10) (1).

The VKORC1 and CYP2C9 genotypes are the most important known genetic determinants of warfarin dosing. Warfarin targets VKORC1, an enzyme involved in vitamin K recycling. A common variant, VKORC1, c. -1639G>A, is associated with an increased sensitivity to warfarin and lower dose requirements. The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*2 and *3, are also associated with lower dose requirements.

VII. APPENDIX 1: U.S. Food & drug administration (FDA) PGx Biomarker in drug labelling

U.S. FOOD & DRUG ADMINISTRATION (FDA) PGX BIOMARKER IN DRUG LABELING

08 FEBRUARY 2018

Therapeutic Drug Area* Biomarker† Labeling Sections

Abacavir Infectious Diseases HLA-B Boxed Warning, Dosage and Administration, Contraindications, Warnings and Precautions

Abemaciclib (1) Oncology ESR Indications and Usage, Adverse Reactions, Clinical Studies

(Hormone Receptor)

Abemaciclib (2) Oncology ERBB2 Indications and Usage, Adverse Reactions, Clinical Studies

(HER2) Ado-Trastuzumab Oncology ERBB2 Indications and Usage, Warnings and Precautions, Adverse Reactions, Emtansine Clinical Pharmacology, Clinical Studies

(HER2)

Afatinib Oncology EGFR Indications and Usage, Dosage and Administration, Adverse Reactions, Clinical Studies

Alectinib Oncology ALK Indications and Usage, Dosage and Administration, Adverse Reactions, Clinical Pharmacology, Clinical Studies

Amitriptyline Psychiatry CYP2D6 Precautions

Anastrozole Oncology ESR, PGR Indications and Usage, Adverse Reactions, Drug Interactions, Clinical Studies

(Hormone Receptor)

Arformoterol (1) Pulmonary UGT1A1 Clinical Pharmacology

Arformoterol (2) Pulmonary CYP2D6 Clinical Pharmacology

Aripiprazole Psychiatry CYP2D6 Dosage and Administration, Use in Specific Populations, Clinical Pharmacology Aripiprazole Psychiatry CYP2D6 Dosage and Administration, Use in Specific Populations, Clinical Lauroxil Pharmacology

Arsenic Trioxide Oncology PML-RARA Indications and Usage Ascorbic Acid, Gastroenterology G6PD Warnings and Precautions PEG-3350, Potassium Chloride, Sodium Ascorbate, Sodium Chloride, and

Sodium Sulfate

Atezolizumab Oncology CD274 Adverse Reactions, Clinical Pharmacology, Clinical Studies

(PD-L1)

Atomoxetine Psychiatry CYP2D6 Dosage and Administration, Warnings and Precautions, Adverse Reactions, Drug Interactions, Clinical Pharmacology

Avelumab Oncology CD274 Clinical Studies (PD-L1)

Azathioprine Rheumatology TPMT Dosage and Administration, Warnings, Precautions, Drug Interactions, Adverse Reactions, Clinical Pharmacology

Belinostat Oncology UGT1A1 Dosage and Administration, Clinical Pharmacology

Blinatumomab Oncology BCR-ABL1 Indications and Usage, Clinical Studies (Philadelphia chromosome)

Boceprevir Infectious Diseases IFNL3 Clinical Pharmacology

(IL28B)

Bosutinib Oncology BCR-ABL1 Indications and Usage, Adverse Reactions, Use in Specific Populations, Clinical Studies

(Philadelphia chromosome) Brentuximab Oncology ALK Clinical Studies

Vedotin

Brexpiprazole Psychiatry CYP2D6 Dosage and Administration, Use in Specific Populations, Clinical Pharmacology

Brigatinib Oncology ALK Indications and Usage, Adverse Reactions, Clinical Studies

Brivaracetam Neurology CYP2C19 Clinical Pharmacology

Busulfan Oncology BCR-ABL1 Clinical Studies (Philadelphia chromosome)

Cabozantinib Oncology RET Clinical Studies

Capecitabine Oncology DPYD Warnings and Precautions, Patient Counseling Information

Carbamazepine (1) Neurology HLA-B Boxed Warning, Warnings, Precautions

Carbamazepine (2) Neurology HLA-A Warnings

Carglumic Acid Inborn Errors of NAGS Indications and Usage, Warnings and Metabolism Precautions, Use in Specific Populations, Clinical Pharmacology, Clinical Studies

Cariprazine Psychiatry CYP2D6 Clinical Pharmacology

Carisoprodol Rheumatology CYP2C19 Use in Specific Populations, Clinical Pharmacology

Carvedilol Cardiology CYP2D6 Drug Interactions, Clinical Pharmacology

Celecoxib Rheumatology CYP2C9 Dosage and Administration, Use in Specific Populations, Clinical Pharmacology

Ceritinib Oncology ALK Indications and Usage, Dosage and Administration, Adverse Reactions, Clinical Studies

Cerliponase Alfa Inborn Errors of TPP1 Indications and Usage, Use in Specific Metabolism Populations, Clinical Studies

Cetuximab (1) Oncology EGFR Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Clinical Studies

Cetuximab (2) Oncology RAS Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Clinical Studies

Cevimeline Dental CYP2D6 Precautions

Chloroquine Infectious Diseases G6PD Precautions

Chlorpropamide Endocrinology G6PD Precautions

Cisplatin Oncology TPMT Adverse Reactions

Citalopram (1) Psychiatry CYP2C19 Dosage and Administration, Warnings, Clinical Pharmacology

Citalopram (2) Psychiatry CYP2D6 Clinical Pharmacology

Clobazam Neurology CYP2C19 Dosage and Administration, Use in Specific Populations, Clinical Pharmacology

Clomipramine Psychiatry CYP2D6 Precautions

Clopidogrel Cardiology CYP2C19 Boxed Warning, Warnings and Precautions, Clinical Pharmacology

Clozapine Psychiatry CYP2D6 Dosage and Administration, Use in Specific Populations, Clinical Pharmacology

Cobimetinib Oncology BRAF Indications and Usage, Dosage and Administration, Adverse Reactions, Clinical Studies

Codeine Anesthesiology CYP2D6 Boxed Warning, Warnings and Precautions, Use in Specific Populations, Patient Counseling Information

Crizotinib (1) Oncology ALK Indications and Usage, Dosage and Administration, Adverse Reactions, Use in Specific Populations, Clinical Pharmacology, Clinical Studies

Crizotinib (2) Oncology ROS1 Indications and Usage, Dosage and Administration, Adverse Reactions, Use in Specific Populations, Clinical Studies

Dabrafenib (1) Oncology BRAF Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Clinical Pharmacology, Clinical Studies, Patient Counseling Information

Dabrafenib (2) Oncology G6PD Warnings and Precautions, Adverse Reactions, Patient Counseling Information

Dabrafenib (3) Oncology RAS Dosage and Administration, Warnings and Precautions

Daclatasvir Infectious Diseases IFNL3 Clinical Studies (IL28B)

Dapsone (1) Dermatology G6PD Warnings and Precautions, Use in Specific Populations

Dapsone (2) Dermatology Nonspecific Warnings and Precautions (Congenital Methemoglobinemia)

Dapsone (3) Infectious Diseases G6PD Precautions, Adverse Reactions, Overdosage

Darifenacin Urology CYP2D6 Clinical Pharmacology Dasabuvir, Infectious Diseases IFNL3 Clinical Studies Ombitasvir, Paritaprevir,

and Ritonavir

(IL28B)

Dasatinib Oncology BCR-ABL1 Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Clinical Studies

(Philadelphia chromosome)

Denileukin Diftitox Oncology IL2RA Indications and Usage, Warnings and Precautions, Clinical Studies

(CD25 antigen)

Desflurane Anesthesiology Nonspecific Contraindications (Genetic Susceptibility to Malignant Hyperthermia)

Desipramine Psychiatry CYP2D6 Precautions

Desvenlafaxine Psychiatry CYP2D6 Clinical Pharmacology

Deutetrabenazine Neurology CYP2D6 Dosage and Administration, Warnings and Precautions, Use in Specific Populations, Clinical Pharmacology

Dexlansoprazole Gastroenterology CYP2C19 Drug Interactions, Clinical Pharmacology Dextromethorphan Neurology CYP2D6 Warnings and Precautions, Clinical Pharmacology and Quinidine

Diazepam Neurology CYP2C19 Clinical Pharmacology

Dinutuximab Oncology MYCN Clinical Studies

Dolutegravir Infectious Diseases UGT1A1 Clinical Pharmacology

Doxepin (1) Psychiatry CYP2D6 Clinical Pharmacology

Doxepin (2) Psychiatry CYP2C19 Clinical Pharmacology

Dronabinol Gastroenterology CYP2C9 Use in Specific Populations, Clinical Pharmacology Drospirenone and Gynecology CYP2C19 Clinical Pharmacology

Ethinyl Estradiol

Duloxetine Psychiatry CYP2D6 Drug Interactions

Durvalumab Oncology CD274 Clinical Pharmacology, Clinical Studies

(PD-L1)

Efavirenz Infectious Diseases CYP2B6 Clinical Pharmacology Elbasvir and Infectious Diseases IFNL3 Clinical Studies

Grazoprevir (IL28B)

Eliglustat Inborn Errors of CYP2D6 Indications and Usage, Dosage and Metabolism Administration, Contraindications, Warnings and Precautions, Drug Interactions, Use in Specific Populations, Clinical Pharmacology, Clinical Studies

Elosulfase Inborn Errors of GALNS Indications and Usage, Warnings and Metabolism Precautions, Use in Specific Populations, Clinical Pharmacology, Clinical Studies

Eltrombopag (1) Hematology F5 Warnings and Precautions (Factor V Leiden)

Eltrombopag (2) Hematology SERPINC1 Warnings and Precautions

(Antithrombin III)

Enasidenib Oncology IDH2 Indications and Usage, Dosage and Administration, Clinical Pharmacology, Clinical Studies

Enflurane Anesthesiology Nonspecific Contraindications (Genetic Susceptibility to Malignant Hyperthermia)

Erlotinib Oncology EGFR Indications and Usage, Dosage and Administration, Adverse Reactions, Clinical Studies Erythromycin and Infectious Diseases G6PD Precautions

Sulfisoxazole

Escitalopram (1) Psychiatry CYP2D6 Drug Interactions

Escitalopram (2) Psychiatry CYP2C19 Adverse Reactions

Esomeprazole Gastroenterology CYP2C19 Drug Interactions, Clinical Pharmacology

Eteplirsen Neurology DMD Indications and Usage, Adverse Reactions, Use in Specific Populations, Clinical Studies

Everolimus (1) Oncology ERBB2 Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Drug Interactions, Use in Specific Populations, Clinical Studies

(HER2)

Everolimus (2) Oncology ESR Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Drug Interactions, Use in Specific Populations, Clinical Studies

(Hormone Receptor)

Exemestane Oncology ESR, PGR Indications and Usage, Dosage and Administration, Clinical Studies

(Hormone Receptor)

Fesoterodine Urology CYP2D6 Drug Interactions, Clinical Pharmacology

Flibanserin (1) Gynecology CYP2C9 Clinical Pharmacology

Flibanserin (2) Gynecology CYP2C19 Adverse Reactions, Use in Specific Populations, Clinical Pharmacology

Flibanserin (3) Gynecology CYP2D6 Clinical Pharmacology

Fluorouracil (1) Dermatology DPYD Contraindications, Warnings

Fluorouracil (2) Oncology DPYD Warnings and Precautions, Patient Counseling Information

Fluoxetine Psychiatry CYP2D6 Precautions, Clinical Pharmacology

Flurbiprofen Rheumatology CYP2C9 Clinical Pharmacology

Fluvoxamine Psychiatry CYP2D6 Drug Interactions

Formoterol (1) Pulmonary CYP2D6 Clinical Pharmacology

Formoterol (2) Pulmonary CYP2C19 Clinical Pharmacology

Fulvestrant (1) Oncology ERBB2 Indications and Usage, Adverse Reactions, Clinical Studies

(HER2)

Fulvestrant (2) Oncology ESR, PGR Indications and Usage, Adverse Reactions, Clinical Pharmacology, Clinical Studies

(Hormone Receptor)

Galantamine Neurology CYP2D6 Clinical Pharmacology

Gefitinib Oncology EGFR Indications and Usage, Dosage and Administration, Clinical Studies

Glimepiride Endocrinology G6PD Warnings and Precautions, Adverse Reactions

Glipizide Endocrinology G6PD Precautions

Glyburide Endocrinology G6PD Precautions

Hydralazine Cardiology Nonspecific Clinical Pharmacology

(NAT)

Ibrutinib (1) Oncology Chromosome 17p Indications and Usage, Clinical Studies

Ibrutinib (2) Oncology Chromosome 11q Clinical Studies

Iloperidone Psychiatry CYP2D6 Dosage and Administration, Warnings and Precautions, Drug Interactions, Clinical Pharmacology

Imatinib (1) Oncology KIT Indications and Usage, Dosage and Administration, Clinical Studies

Imatinib (2) Oncology BCR-ABL1 Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Use in Specific Populations, Clinical Pharmacology, Clinical Studies

(Philadelphia chromosome)

Imatinib (3) Oncology PDGFRB Indications and Usage, Dosage and Administration, Clinical Studies

Imatinib (4) Oncology FIP1L1-PDGFRA Indications and Usage, Dosage and Administration, Clinical Studies

Imipramine Psychiatry CYP2D6 Precautions

Indacaterol Pulmonary UGT1A1 Clinical Pharmacology Inotuzumab Oncology BCR-ABL1 Clinical Studies

Ozogamicin (Philadelphia chromosome)

Irinotecan Oncology UGT1A1 Dosage and Administration, Warnings and Precautions, Clinical Pharmacology

Isoflurane Anesthesiology Nonspecific Contraindications (Genetic Susceptibility to Malignant Hyperthermia) Isoniazid, Infectious Diseases Nonspecific Clinical Pharmacology Pyrazinamide, and

Rifampin (NAT) Isosorbide Cardiology CYB5R Overdosage

Dinitrate Isosorbide Cardiology CYB5R Overdosage

Mononitrate

Ivacaftor Pulmonary CFTR Indications and Usage, Adverse Reactions, Use in Specific Populations, Clinical Pharmacology, Clinical Studies Ivacaftor and Pulmonary CFTR Indications and Usage, Adverse Reactions, Use in Specific Lumacaftor Populations, Clinical Studies

Lacosamide Neurology CYP2C19 Clinical Pharmacology

Lansoprazole Gastroenterology CYP2C19 Drug Interactions, Clinical Pharmacology

Lapatinib (1) Oncology ERBB2 Indications and Usage, Dosage and Administration, Adverse Reactions, Use in Specific Populations, Clinical Studies

(HER2)

Lapatinib (2) Oncology ESR, PGR Indications and Usage, Dosage and Administration, Adverse Reactions, Use in Specific Populations, Clinical Studies

(Hormone Receptor)

Lapatinib (3) Oncology HLA-DQA1, HLA-DRB1 Clinical Pharmacology Ledipasvir and Infectious Diseases IFNL3 Clinical Studies

Sofosbuvir (IL28B)

Lenalidomide Hematology Chromosome 5q Boxed Warning, Indications and Usage, Adverse Reactions, Use in Specific Populations, Clinical Studies

Lesinurad Rheumatology CYP2C9 Drug Interactions, Clinical Pharmacology

Letrozole Oncology ESR, PGR Indications and Usage, Adverse Reactions, Clinical Studies

(Hormone Receptor) Lidocaine and Anesthesiology Nonspecific Warnings and Precautions

Prilocaine (1) (Congenital Methemoglobinemia)

Lidocaine and Anesthesiology G6PD Warnings and Precautions, Clinical Pharmacology Prilocaine (2)

Mafenide Infectious Diseases G6PD Warnings, Adverse Reactions

Mercaptopurine Oncology TPMT Dosage and Administration, Warnings, Precautions, Adverse Reactions, Clinical Pharmacology

Methylene Blue Hematology G6PD Contraindications, Warnings and Precautions Metoclopramide Gastroenterology CYB5R Precautions, Overdosage

(1)

Metoclopramide Gastroenterology G6PD Precautions, Overdosage

(2)

Metoprolol Cardiology CYP2D6 Drug Interactions, Clinical Pharmacology

Midostaurin (1) Oncology FLT3 Indications and Usage, Dosage and Administration, Adverse Reactions, Clinical Studies

Midostaurin (2) Oncology NPM1 Clinical Studies

Midostaurin (3) Oncology KIT Clinical Studies

Mirabegron Urology CYP2D6 Clinical Pharmacology

Modafinil Psychiatry CYP2D6 Clinical Pharmacology

Mycophenolic Acid Transplantation HPRT1 Warnings and Precautions

Nalidixic Acid Infectious Diseases G6PD Precautions, Adverse Reactions

Nebivolol Cardiology CYP2D6 Dosage and Administration, Clinical Pharmacology

Nefazodone Psychiatry CYP2D6 Precautions

Neratinib (1) Oncology ERBB2

Indications and Usage, Adverse Reactions, Clinical Studies

(HER2)

Neratinib (2) Oncology ESR, PGR Clinical Studies (Hormone Receptor)

Nilotinib (1) Oncology BCR-ABL1 Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Use in Specific Populations, Clinical Studies

(Philadelphia chromosome)

Nilotinib (2) Oncology UGT1A1 Clinical Pharmacology

Niraparib Oncology BRCA Clinical Studies

Nitrofurantoin Infectious Diseases G6PD Warnings, Adverse Reactions

Nivolumab (1) Oncology BRAF Indications and Usage, Adverse Reactions, Clinical Studies

Nivolumab (2) Oncology CD274 Clinical Pharmacology, Clinical Studies

(PD-L1)

Nivolumab (3) Oncology Microsatellite Instability, Indications and Usage, Use in Specific Mismatch Repair Populations, Clinical Pharmacology, Clinical Studies

Nortriptyline Psychiatry CYP2D6 Precautions

Obinutuzumab Oncology MS4A1 Clinical Studies (CD20 antigen)

Olaparib Oncology BRCA Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Clinical Studies

Olaratumab Oncology PDGFRA Clinical Studies

Omacetaxine Oncology BCR-ABL1 Clinical Studies (Philadelphia chromosome) Ombitasvir, Infectious Diseases IFNL3 Clinical Studies Paritaprevir, and

Ritonavir (IL28B)

Omeprazole Gastroenterology CYP2C19 Drug Interactions, Clinical Pharmacology

Ondansetron Gastroenterology CYP2D6 Clinical Pharmacology

Osimertinib Oncology EGFR Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Clinical Studies

Oxcarbazepine Neurology HLA-B Warnings and Precautions

Palbociclib (1) Oncology ESR Indications and Usage, Adverse Reactions, Clinical Studies

(Hormone Receptor)

Palbociclib (2) Oncology ERBB2 Indications and Usage, Adverse Reactions, Clinical Studies

(HER2)

Palonosetron Gastroenterology CYP2D6 Clinical Pharmacology

Panitumumab (1) Oncology EGFR Adverse Reactions, Clinical Pharmacology, Clinical Studies

Panitumumab (2) Oncology RAS Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Clinical Studies

Pantoprazole Gastroenterology CYP2C19 Clinical Pharmacology Parathyroid Inborn Errors of CASR Indications and Usage, Clinical Metabolism Studies Hormone

Paroxetine Psychiatry CYP2D6 Drug Interactions

Pazopanib (1) Oncology UGT1A1 Clinical Pharmacology

Pazopanib (2) Oncology HLA-B Clinical Pharmacology Peginterferon Alfa- Infectious Diseases IFNL3 Clinical Pharmacology

2b (IL28B)

Pegloticase Rheumatology G6PD Boxed Warning, Contraindications, Warnings and Precautions, Patient Counseling Information

Pembrolizumab (1) Oncology BRAF Adverse Reactions, Clinical Studies

Pembrolizumab (2) Oncology CD274 Indications and Usage, Dosage and Administration, Use in Specific Populations, Clinical Studies

(PD-L1)

Pembrolizumab (3) Oncology Microsatellite Instability, Indications and Usage, Mismatch Repair Dosage and Administration, Use in Specific Populations, Clinical Studies

Perphenazine Psychiatry CYP2D6 Precautions, Clinical Pharmacology

Pertuzumab (1) Oncology ERBB2 Indications and Usage, Warnings and Precautions, Adverse Reactions, Clinical Pharmacology, Clinical Studies

(HER2)

Pertuzumab (2) Oncology ESR, PGR Clinical Studies (Hormone Receptor)

Phenytoin (1) Neurology CYP2C9 Clinical Pharmacology

Phenytoin (2) Neurology CYP2C19 Clinical Pharmacology

Phenytoin (3) Neurology HLA-B Warnings

Pimozide Psychiatry CYP2D6 Dosage and Administration, Precautions

Piroxicam Rheumatology CYP2C9 Clinical Pharmacology

Ponatinib Oncology BCR-ABL1 Indications and Usage, Warnings and Precautions, Adverse Reactions, Use in Specific Populations, Clinical Studies

(Philadelphia chromosome)

Prasugrel (1) Cardiology CYP2C19 Use in Specific Populations, Clinical Pharmacology, Clinical Studies

Prasugrel (2) Cardiology CYP2C9 Use in Specific Populations, Clinical Pharmacology, Clinical Studies

Prasugrel (3) Cardiology CYP3A5 Use in Specific Populations, Clinical Pharmacology, Clinical Studies

Prasugrel (4) Cardiology CYP2B6 Use in Specific Populations, Clinical Pharmacology, Clinical Studies

Primaquine (1) Infectious Diseases G6PD Contraindications, Warnings, Precautions, Adverse Reactions, Overdosage

Primaquine (2) Infectious Diseases CYB5R Precautions, Adverse Reactions

Propafenone Cardiology CYP2D6 Dosage and Administration, Warnings and Precautions, Drug Interactions, Clinical Pharmacology

Propranolol Cardiology CYP2D6 Clinical Pharmacology

Protriptyline Psychiatry CYP2D6 Precautions

Quinidine Cardiology CYP2D6 Precautions

Quinine Sulfate (1) Infectious Diseases G6PD Contraindications

Quinine Sulfate (2) Infectious Diseases CYP2D6 Drug Interactions

Rabeprazole Gastroenterology CYP2C19 Clinical Pharmacology

Rasburicase (1) Oncology G6PD Boxed Warning, Contraindications, Warnings and Precautions

Rasburicase (2) Oncology CYB5R Boxed Warning, Contraindications, Warnings and Precautions

Ribociclib (1) Oncology ESR, PGR Indications and Usage, Clinical Studies (Hormone Receptor)

Ribociclib (2) Oncology ERBB2 Indications and Usage, Clinical Studies

(HER2)

Risperidone Psychiatry CYP2D6 Drug Interactions, Clinical Pharmacology

Rituximab Oncology MS4A1 Indications and Usage, Dosage and Administration, Adverse Reactions, Use in Specific Populations, Clinical Studies

(CD20 antigen)

Rosuvastatin Endocrinology SLCO1B1 Clinical Pharmacology

Rucaparib (1) Oncology BRCA Indications and Usage, Dosage and Administration, Adverse Reactions, Use in Specific Populations, Clinical Studies

Rucaparib (2) Oncology CYP2D6 Clinical Pharmacology

Rucaparib (3) Oncology CYP1A2 Clinical Pharmacology

Sevoflurane Anesthesiology Nonspecific Warnings (Genetic Susceptibility to Malignant Hyperthermia)

Simeprevir Infectious Diseases IFNL3 Clinical Pharmacology, Clinical Studies

(IL28B)

Sodium Nitrite Toxicology G6PD Warnings and Precautions

Sofosbuvir Infectious Diseases IFNL3 Clinical Studies (IL28B) Sofosbuvir and Infectious Diseases IFNL3 Clinical Studies

Velpatasvir (IL28B) Sofosbuvir, Infectious Diseases IFNL3 Clinical Studies Velpatasvir, and

Voxilaprevir

(IL28B)

Succimer Hematology G6PD Clinical Pharmacology

Succinylcholine Anesthesiology BCHE Warnings, Precautions Sulfamethoxazole Infectious Diseases G6PD Precautions and Trimethoprim

(1) Sulfamethoxazole Infectious Diseases Nonspecific Precautions and Trimethoprim

(2) (NAT)

Sulfasalazine (1) Gastroenterology G6PD Precautions

Sulfasalazine (2) Gastroenterology Nonspecific Clinical Pharmacology

(NAT)

Tamoxifen (1) Oncology ESR, PGR Indications and Usage, Precautions, Adverse Reactions, Clinical Studies

(Hormone Receptor)

Tamoxifen (2) Oncology F5 Warnings (Factor V Leiden)

Tamoxifen (3) Oncology F2 Warnings (Prothrombin)

Telaprevir Infectious Diseases IFNL3 Clinical Pharmacology, Clinical Studies

(IL28B)

Tetrabenazine Neurology CYP2D6 Dosage and Administration, Warnings and Precautions, Use in Specific Populations, Clinical Pharmacology

Thioguanine Oncology TPMT Dosage and Administration, Warnings, Precautions

Thioridazine Psychiatry CYP2D6 Contraindications, Warnings, Precautions

Ticagrelor Cardiology CYP2C19 Clinical Pharmacology

Tolterodine Urology CYP2D6 Precautions, Clinical Pharmacology

Tramadol Anesthesiology CYP2D6 Boxed Warning, Warnings, Precautions, Use in Specific Populations, Clinical Pharmacology

Trametinib (1) Oncology BRAF Indications and Usage, Dosage and Administration, Adverse Reactions, Clinical Pharmacology, Clinical Studies, Patient Counseling Information

Trametinib (2) Oncology G6PD Adverse Reactions

Trametinib (3) Oncology RAS Warnings and Precautions

Trastuzumab (1) Oncology ERBB2 Indications and Usage, Warnings and Precautions, Clinical Pharmacology, Clinical Studies

(HER2)

Trastuzumab (2) Oncology ESR, PGR Clinical Studies (Hormone Receptor)

Tretinoin Oncology PML-RARA Indications and Usage, Warnings, Clinical Pharmacology

Trimipramine Psychiatry CYP2D6 Precautions

Umeclidinium Pulmonary CYP2D6 Clinical Pharmacology

Ustekinumab Dermatology and IL12A, IL12B, IL23A Warnings and Precautions Gastroenterology

Valbenazine Neurology CYP2D6 Dosage and Administration, Warnings and Precautions, Use in Specific Populations, Clinical Pharmacology

Valproic Acid (1) Neurology POLG Boxed Warning, Contraindications, Warnings and Precautions

Valproic Acid (2) Neurology Nonspecific Contraindications, Warnings and Precautions

(Urea Cycle Disorders)

Vemurafenib (1) Oncology BRAF Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Use in Specific Populations, Clinical Pharmacology, Clinical Studies, Patient Counseling Information

Vemurafenib (2) Oncology RAS Warnings and Precautions, Adverse Reactions

Venetoclax Oncology Chromosome 17p Indications and Usage, Dosage and Administration, Use in Specific Populations, Clinical Studies

Venlafaxine Psychiatry CYP2D6 Precautions

Voriconazole Infectious Diseases CYP2C19 Clinical Pharmacology

Vortioxetine Psychiatry CYP2D6 Dosage and Administration, Clinical Pharmacology

Warfarin (1) Hematology CYP2C9 Dosage and Administration, Drug Interactions, Clinical Pharmacology

Warfarin (2) Hematology VKORC1 Dosage and Administration, Clinical Pharmacology

Warfarin (3) Hematology PROS1 Warnings and Precautions

Warfarin (4) Hematology PROC Warnings and Precautions

VIII. APPENDIX 2: Genetic biomarkers associated with inter-individual differences in drug pharmacokinetic or pharmacodynamics parameters

U.S. FOOD & DRUG ADMINISTRATION (FDA) GENETIC BIOMARKERS ASSOCIATED WITH INTER- INDIVIDUAL DIFFERENCES IN DRUG PHARMACOKINETIC OR PHARMACODYNAMICS PARAMETERS.

08 FEBRUARY 2018.

Sherri J. Willard Argyres, MA, PharmD, BCPS, is a senior clinical content specialist for Wolters Kluwer Clinical Drug Information.

Efficacy or Safety Drug Gene Phenotype Recommendation Outcome of Concern HLA-B*57:01 Increased risk of Abacavir HLA-B High Risk Alternative therapy hypersensitivity reactions Allele Increased risk of adverse CYP2D6 Poor Aripiprazole CYP2D6 effects (eg, extrapyramidal Dosage adjustment Metabolizer symptoms) Increased risk of adverse CYP2D6 Poor reactions (eg, insomnia, Atomoxetine CYP2D6 Dosage adjustment Metabolizer decreased appetite, tremor)

Alternative therapy or dosage Deficient Increased risk of Azathioprine TPMT adjustment and Activity myelotoxicity increased monitoring

Dosage adjustment Intermediate Increased risk of Azathioprine TPMT and increased Activity myelotoxicity monitoring

Increased risk of dose- Reduced limiting toxicities (eg, Belinostat UGT1A1 Dosage adjustment Glucorindation fatigue, atrial fibrillation, and diarrhea) CYP2D6 Poor Increased risk of Brexpiprazole CYP2D6 Dosage adjustment Metabolizer akasthisia Increased risk of severe, life-threatening, or fatal DPD Deficient adverse reactions (eg, Capecitabine DPYD Alternative therapy Activity mucositis, diarrhea, neutropenia, and neurotoxicity)

Increased risk of severe, life-threatening, or fatal DPD Alternative therapy adverse reactions (eg, Capecitabine DPYD Intermediate or dosage mucositis, diarrhea, Activity adjustment neutropenia, and neurotoxicity) Increased risk of hypersensitivity syndrome, drug reaction with HLA-A*31:01 eosinophilia and systemic Carbamazepine HLA-A High Risk Alternative therapy symptoms (DRESS) and Allele maculopapular exanthema (MPE) cutaneous reactions HLA-B*15:02 Increased risk of Stevens Carbamazepine HLA-B High Risk Johnson syndrome/toxic Alternative therapy Allele epidermal necrolysis Increased risk of Dosage adjustment CYP2C9 Poor cardiovascular or Celecoxib CYP2C9 or alternative Metabolizer gastrointestinal adverse therapy events CYP2C19 Poor Increased risk of QT Citalopram CYP2C19 Dosage adjustment Metabolizer prolongation Increased risk of cardiovascular CYP2C19 Poor complications related to Clopidogrel CYP2C19 Alternative therapy Metabolizer acute coronary syndrome or percutaneous coronary intervention CYP2D6 Poor Increased risk of PR, QT, Eliglustat CYP2D6 Dosage adjustment Metabolizer QRS prolongation CYP2D6 Poor Increased risk of Eliglustat CYP2D6 Alternative therapy Metabolizer therapeutic failure Increased risk of CYP2C19 Poor hypotension, syncope, Increased Flibanserin CYP2C19 Metabolizer and central nervous monitoring system depression Increased risk of severe, life-threatening, or fatal DPD Deficient adverse reactions (eg, Fluorouracil DPYD Alternative therapy Activity mucositis, diarrhea, neutropenia, and neurotoxicity) Increased risk of severe, life-threatening, or fatal DPD Alternative therapy adverse reactions (eg, Fluorouracil DPYD Intermediate or dosage mucositis, diarrhea, Activity adjustment neutropenia, and neurotoxicity) CYP2D6 Poor Increased risk of QT Iloperidone CYP2D6 Dosage adjustment Metabolizer prolongation UGT1A1 Increased risk of Irinotecan UGT1A1 Reduced neutropenia and/or life Dosage adjustment Activity threatening diarrhea

Alternative therapy or dosage TPMT Deficient Increased risk of Mercaptopurine (6-MP) TPMT adjustment and Activity myelosuppression increased monitoring

Increased risk of Stevens HLA-B*15:02 Oxcarbazepine HLA-B Johnson syndrome/toxic Alternative therapy High Risk epidermal necrolysis Increased risk of Stevens HLA-B*15:02 Phenytoin/Fosphenytoin HLA-B Johnson syndrome/toxic Alternative therapy High Risk epidermal necrolysis CYP2D6 Poor Inreased risk of QT Pimozide CYP2D6 Dosage adjustment Metabolizer prolongation

Dosage adjustment TPMT Deficient Increased risk of Thioguanine TPMT and increased Activity myelosuppression monitoring

CYP2D6 Poor Increased exposure to Vortioxetine CYP2D6 Dosage adjustment Metabolizer vortioxetine CYP2C9 Poor Warfarin CYP2C9 Increased risk of bleeding Dosage adjustment Metabolizer VKORC Warfarin VKORC1 Warfarin Increased risk of bleeding Dosage adjustment Sensitive

* Therapeutic areas do not necessarily reflect the CDER review division.

† Representative biomarkers are listed based on standard nomenclature as per the Human Genome Organization (HUGO) symbol and/or simplified descriptors using other common conventions. Listed biomarkers do not necessarily reflect the terminology used in labeling. The term “Nonspecific” is provided when labeling does not explicitly identify the specific biomarker(s) or when the biomarker is represented by a molecular phenotype or gene signature, and in some cases the biomarker was inferred based on the labeling language.

URL: https://www.fda.gov/Drugs/ScienceResearch/ucm572698.htm

U.S. Food and Drug Administration. 10903 New Hampshire Avenue. Silver Spring, MD 20993. 1-888- INFO-FDA (1-888-463-6332)