pharmacogenomics and personalized therapy .pptx

pharmacogenomics, pharmacology, and personalized medicine

1. Pharmacogenetics and Personalized Therapy: Advancing Drug Therapy Welcome to this presentation exploring the exciting field of pharmacogenetics and its impact on personalized therapy. We'll delve into the science behind how genes influence drug responses, explore the promises and challenges of this transformative approach to medicine, and showcase real-world examples of its success. Presented by: Omer Muhammed Asaad Supervised by: Assit . Prof. Nidhal Muhammed Ali

2. Outlines: Introduction to Pharmacogenetics The Promise of Personalized Medicine Pharmacogenetics vs. Pharmacogenomics The Pharmacogenomics Knowledge Base ( PharmGKB ) Individual variations Key Genes in Drug Metabolism CYP2D6 and Drug Metabolism CYP2C9 and Drug Metabolism CYP2C19 and Drug Metabolism GENETIC VARIATION Integrating Pharmacogenetics into Clinical applications The Future of Medicine

3. Introduction to Pharmacogenetics Pharmacogenetics is the study of how genetic variation impacts the pharmacokinetic and pharmacodynamic properties of an administered drug. ( Pian et al., 2017)

4. Introduction to Pharmacogenetics The Genetic Testing Registry (GTR) in the United States accepts submissions from laboratories worldwide regarding the genetic tests that are made available for the purposes of screening, diagnosis, drug/disease monitoring and treatment response.

5. Introduction to Pharmacogenetics Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose. Drug labeling may contain information on genomic biomarkers and can describe: Drug exposure and clinical response variability Risk for adverse events Genotype-specific dosing Polymorphic drug target and disposition genes

6. The Promise of Personalized Medicine: Matching Therapies to Genotypes Personalized medicine holds the promise of revolutionizing healthcare by tailoring treatment plans based on each patient's unique genetic makeup. This approach moves away from a one-size-fits-all strategy, aiming to improve drug efficacy and safety while minimizing adverse effects. By understanding an individual's genetic profile, doctors can select the most appropriate medications and adjust doses to optimize therapeutic outcomes. This personalized approach aims to increase the likelihood of successful treatment while minimizing side effects and drug interactions. Furthermore, personalized medicine has the potential to reduce healthcare costs by preventing unnecessary hospitalizations and complications associated with ineffective or poorly tolerated medications.

7. The Promise of Personalized Medicine Shifting from " one-size-fits-all " to tailored treatments. Reducing adverse drug reactions and improving efficacy. Genes influence pharmacokinetics by altering drug ADME-related proteins. Genes influence pharmacodynamics through variations in drug targets: G proteins or other downstream pathways. Genetic differences also contribute to rare adverse reactions. Genetic information may soon enable precise drug selection, ensuring efficacy and safety while reducing trial-and-error prescribing—an approach known as personalized medicine.

8. Role of FDA in Pharmacogenetics The US FDA has approved over 608 pharmacogenomic biomarkers by 2025 for inclusion in drug labeling, guiding personalized therapy and improving drug safety and efficacy. Inclusion of Pharmacogenomics ( PGx ) information in drug labels has increased for all clinical areas over the last two decades but most prominently for cancer therapies, which comprise the largest proportion (75.5%) of biomarker–drug pairs for which PGx testing is required. 

9. Pharmacogenetics vs. Pharmacogenomics Pharmacogenetics: Focuses on single genes affecting drug response. Pharmacogenomics: Broader approach involving entire genomes.

10. Pharmacogenetics vs. Pharmacogenomics The European Agency for the Evaluation of Medicinal Products (EMEA) defines “pharmacogenetics” as “the study of interindividual variations in DNA sequence related to drug response” “pharmacogenomics” as “the study of the variability of the expression of individual genes relevant to disease susceptibility as well as drug response at cellular, tissue, individual or population level” (The European Agency for the Evaluation of Medicinal Products (EMEA), 2002).

11. Trends in the number of new biomarker–drug pairs approved per year with annual proportions by cancer vs. non-cancer from 2000 to 2020. Data shown through July of 2020.

12. The Pharmacogenomics Knowledge Base (PharmGKB): A Vital Resource The PharmGKB is a comprehensive database that provides information on the genetic basis of drug response. It houses a wealth of data on genes, drugs, and their interactions, serving as a valuable resource for researchers, clinicians, and patients. The PharmGKB allows users to search for specific genes, drugs, or drug-gene interactions. It provides detailed information on the clinical implications of genetic variations, helping clinicians make informed decisions about drug selection and dosage. The PharmGKB also includes educational resources and tools to promote the understanding and application of pharmacogenomics. It plays a vital role in advancing personalized medicine by facilitating knowledge sharing and collaboration among healthcare professionals.

13. Enhancing Drug Safety and Efficacy: The Role of Pharmacogenetic Testing Pharmacogenetic testing can significantly improve drug safety by identifying patients at risk for adverse reactions. This information allows doctors to choose alternative medications or adjust dosages to minimize the risk of complications. By identifying patients who are likely to respond well to specific medications, pharmacogenetic testing can enhance drug efficacy, ensuring that individuals receive the most effective treatment for their condition. Pharmacogenetic testing can also help reduce healthcare costs by minimizing unnecessary hospitalizations, medication changes, and other complications associated with ineffective or poorly tolerated medications.

14. Individual variation Variability is a serious problem; if not considered, it can result in: • Lack of efficacy • Unexpected harmful effects Main causes of variability: • Age • Genetic factors • Immunological factors • Disease (especially conditions affecting drug metabolism or elimination, e.g., kidney or liver disease) • Drug interactions

15. Pharmacokinetic variation : can occur because of differences in absorption, distribution, metabolism or excretion. Pharmacodynamic variation : refers to how individuals respond differently to drugs. Some drugs, like vaccines and oral contraceptives, have predictable responses allowing for standard doses. However, drugs like lithium, antihypertensives, and anticoagulants often require personalized dosing, adjusted based on plasma drug levels, effects (e.g., blood pressure changes), and potential side effects. Individual variation

16. Individual variation due to Age

17. Key Genes in Pharmacogenetic Testing: CYP2D6, CYP2C9, and CYP2C19 CYP450 enzymes play a crucial role. There are over 50 of these isozymes, 7 of which are involved in metabolizing over 80% of medication. Genetic polymorphisms affect drug metabolism and response. Currently, there are three main types of metabolizers a person can be classified under: Poor metabolizer. Intermediate metabolizer. Extensive metabolizer Ultra-rapid metabolizer.

18. Key Genes in Pharmacogenetic Testing: CYP2D6, CYP2C9, and CYP2C19 1 CYP2D6 is a key enzyme involved in the metabolism of a wide range of drugs, including antidepressants, antipsychotics, and pain relievers. Variations in CYP2D6 can lead to either rapid or slow drug metabolism, influencing drug efficacy and side effects. 2 CYP2C9 plays a crucial role in metabolizing warfarin, a blood thinner, and other medications. Genetic variations in CYP2C9 can alter the rate of warfarin breakdown, affecting its therapeutic effect and potentially increasing the risk of bleeding complications. 3 CYP2C19 is involved in the metabolism of proton pump inhibitors, used for heartburn and ulcers, as well as other medications. Variations in CYP2C19 can affect drug metabolism and may impact drug efficacy or increase the risk of adverse reactions.

19. Individual variation due to Disease Therapeutic drugs are prescribed to patients, making the impact of disease on drug response crucial, especially in conditions affecting major organs responsible for drug metabolism and excretion. Diseases Affecting Receptors: • Myasthenia gravis : Autoimmune disease with antibodies against nicotinic acetylcholine receptors, leading to increased sensitivity to neuromuscular-blocking agents (e.g., vecuronium) and aminoglycoside antibiotics. • X-linked nephrogenic diabetes insipidus : Characterized by abnormal vasopressin (ADH) receptors, causing insensitivity to ADH. • Familial hypercholesterolemia : An inherited LDL receptor disorder; homozygous form resists statin therapy, while the heterozygous form responds well.

20. Diseases Affecting Signal Transduction: • Pseudohypoparathyroidism : Results from impaired G protein–coupled receptor signaling with adenylyl cyclase. • Familial precocious puberty & hyperthyroidism : Caused by mutations in G protein–coupled receptors, leading to continuous receptor activation even without natural hormone stimulation. Individual variation due to Disease

21. GENETIC VARIATION Mutations are heritable changes in the DNA base sequence, which may or may not alter the amino acid sequence of the corresponding protein. Germline or hereditary mutations affect reproductive cells (egg or sperm) and are passed to the next generation, being present in all cells of the offspring. (less significant in clinical practice). Somatic or acquired mutations are not present at birth but can occur in any of the body cells (except the ova and sperm) during a lifetime, and are not passed on to the offspring. (majority not significant in clinical practice except those involved in cell growth, division, and differentiation can predispose individuals to carcinogenesis, such mutations guides drug selection)

22. PLASMA CHOLINESTERASE DEFICIENCY Suxamethonium sensitivity is due to genetic variation in the rate of drug metabolism, resulting from a Mendelian autosomal recessive trait. This short-acting neuromuscular-blocking drug is widely used in anesthesia and is normally rapidly hydrolyzed by plasma cholinesterase. About 1 in 3,000 individuals fail to inactivate Suxamethonium rapidly and experience prolonged neuromuscular block when treated with it. This occurs because a recessive gene produces an abnormal type of plasma cholinesterase. The abnormal enzyme has a modified pattern of substrate and inhibitor specificity. It can be detected by a blood test that measures the effect of dibucaine , which inhibits the abnormal enzyme less effectively than the normal enzyme.

23. PLASMA CHOLINESTERASE DEFICIENCY They appear completely healthy unless exposed to suxamethonium or mivacurium (which is also inactivated by plasma cholinesterase), but experience prolonged paralysis if exposed to a dose that would cause neuromuscular block for only a few minutes in a healthy person. It is important to check the family history and test family members who may be affected. However, the disorder is so rare that it is currently impractical to screen for it routinely before the therapeutic use of suxamethonium .

24. Integrating Pharmacogenetics into Clinical applications . Clinical tests to predict drug responsiveness were among the earliest anticipated applications of human genome sequencing. New pharmacogenetic tests must demonstrate a positive or meaningful impact on prescribing practices, such as guiding the selection of an alternative drug or adjusting the dosing regimen to achieve measurable improvements in patient outcomes (Khoury & Galea, 2016).

25. Integrating Pharmacogenetics into Clinical applications. Pharmacogenetic evaluation can include tests for: • HLA Variants – Associated with severe drug reactions due to immunological interactions. Human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encode cell-surface proteins responsible for regulation of the immune system. • Genes controlling aspects of drug metabolism. • Genes encoding drug targets, where FDA defines them as tests guiding drug selection based on pharmacogenetic markers ( Ko et al., 2015)

26. Integrating Pharmacogenetics into Clinical applications . Pharmacogenetics are incorporated into daily clinical workflows and the main area of Application are: INDICATIONS: where genetic information helps us decide whether the particular drug is indicated, or not.  Dosage adjustment based on genetic predictors of drug metabolism: highlight two prominent examples where dosing schedule is can be guided by evaluation of genetic variants. Screening out patients who are highly susceptible to serious adverse drug reactions. Communicating the presence or absence of risk.

27. Pharmacogenetics in Clinical applications: indication Trastuzumab (Herceptin) is a monoclonal antibody that antagonises epidermal growth factor (EGF) by binding to one of its receptors (human EGF receptor 2 - HER2) which can occur in tumour tissue as a result of somatic mutation. It is used in patients with breast cancer whose tumour tissue is positive for this receptor.

28. Pharmacogenetics in Clinical applications: indication Dasatinib and imatinib are first-line tyrosine kinase inhibitors used in haematological malignancies characterised by the presence of a Philadelphia chromosome, namely chronic myeloid leukaemia (CML) and in some adults with acute lymphocytic leukaemia (ALL). The Philadelphia chromosome results from a translocation defect when parts of two chromosomes (9 and 22) swap places; part of a 'breakpoint cluster region' (BCR) in chromosome 22 links to the 'Abelson-1' (ABL) region of chromosome 9.

29. Pharmacogenetics in Clinical applications: indication A mutation (T3151) in BCR/ABL confers resistance to the inhibitory effect of dasatinib and patients with this variant do not benefit from this drug. Instead, ponatinib is licensed in the United States for treatment of patients who have this BCR-ABL T3151 mutation.

30. Pharmacogenetics in Clinical applications: indication There are now small-molecule-based treatments specifically targeted at patients with certain defined inherited conditions. These include: Givosiran (GIVLAARI) indicated for the treatment of adults with acute hepatic porphyria (AHP). Eteplersen (Exondys-51): an antisense oligomer that acts on mRNA to restore dystrophin production, for patients with highly specific mutations that cause Duchenne/Becker muscular dystrophy (DMD). The recommended dose of GIVLAARI is 2.5 mg/kg administered via subcutaneous injection once monthly by HCPs.  

31. Pharmacogenetics in Clinical applications: dosage adjustment Thiopurine Drugs: • Tioguanine , Mercaptopurine , and Azathioprine are used for leukemias and immunosuppression in inflammatory disorders (bowel, skin, joints). • These drugs are detoxified by thiopurine-S-methyltransferase ( TPMT ) and xanthine oxidase. • Genetic variants in TPMT affect drug metabolism. • Reduced doses recommended for patients with low TPMT activity. • Genetic testing helps but does not eliminate toxicity risks. White blood cell count must be closely monitored, as environmental factors also impact toxicity. ( Weinshilboum and Sladek , 1980).

32. Pharmacogenetics of 5-FU and Related Drugs 5-Fluorouracil (5-FU), Capecitabine, Tegafur • Used for solid tumors but have a narrow therapeutic window. • Toxicity Risks: • 10%-40% of patients experience severe side effects (neutropenia, vomiting, diarrhea, mucocutaneous syndromes). • Fatality rate: ~1 in 100. • 80% of 5-FU is detoxified by dihydropyrimidine dehydrogenase ( DPYD ). • Four major DPYD variants contribute to 20%-30% of life-threatening toxicity cases. Clinical Application: • Genetic testing guides dose reductions and gradual dose increments. • May help select alternative chemotherapy for high-risk patients.

33. Pharmacogenetics in Clinical applications: Screening Abacavir (HIV Treatment) • Reverse transcriptase inhibitor effective for HIV. • Its use has been limited by severe rashes. Susceptibility to this adverse effect is closely linked to the HLA variant HLAB*5701 . • Genetic testing is now standard of care to prevent hypersensitivity reactions. (Martin and Kroetz , 2013).

34. Pharmacogenetics in Clinical applications: Screening Carbamazepine and HLA-B*1502 Screening • Carbamazepine can cause severe Skin Reactions such as: • Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN). • Characterized by painful blistering, skin detachment, and potential gastrointestinal involvement. • Strongly linked to HLA-B*1502 allele. • More common in Thailand, Malaysia, and Taiwan. • Less frequent in Korean, Japanese, and White populations. • HLA-B*1502 screening prevents carbamazepine-induced SJS ( Barbarinoet al., 2015).

35. Pharmacogenetics in Clinical applications: Communicating the presence or absence of risk a particular drug may have been specifically tested in people with different genetic variants, and there may be information on extent of risk, if any. lacosamide (used in the treatment of epilepsy): no clinically relevant difference in lacosamide exposure when comparing extensive metabolizers against poor metabolizers according to CYP2C19 status

36. The Future of Medicine: Integrating Pharmacogenetics into Clinical Practice The future of medicine holds great promise for personalized therapy as pharmacogenetics becomes increasingly integrated into clinical practice. The ongoing advancements in genomic sequencing, bioinformatics, and drug development will further refine and expand the applications of pharmacogenetics, leading to more effective and safer treatments for a wide range of conditions. This paradigm shift in healthcare will empower patients and clinicians to work together, leveraging the power of individual genetic information to optimize health outcomes.

37. References  Rang, H. P., Dale, M. M., Ritter, J. M., Flower, R. J., & Henderson, G. (2023).  Rang & Dale's Pharmacology . 10th ed. Elsevier. PharmGKB . (2024).  Pharmacogenomics Knowledge Base . Available at: https:// www.pharmgkb.org / [Accessed 24 Feb 2025]. FDA. (2025).  Table of Pharmacogenetic Biomarkers in Drug Labeling . Available at: https:// www.fda.gov /[Accessed 24 Feb 2025]. Barbarino , J.M., Kroetz , D.L., Klein, T.E., Altman, R.B., 2015. PharmGKB Summary: Very Important Pharmacogene Information for Human Leukocyte Antigen B (HLA-B). Pharmacogenet . Genomics 25, 205–221. https:// doi.org /10.1097/FPC.0000000000000118 Gonzales, A., Collantes -Silva, N., Arambulo-Castillo, S., Ortiz- Benique , Z.N., Alarcon, E., 2024. Abstract 4140060: Impact of SGLT2 Inhibitors on Mortality Risk in Type 2 Diabetes Mellitus and Coronary Artery Disease: A Systematic Review and Meta-Analysis. Circulation 150. https:// doi.org /10.1161/circ.150.suppl_1.4140060 Khoury, M.J., Galea, S., 2016. Will Precision Medicine Improve Population Health? JAMA 316, 1357–1358. https:// doi.org /10.1001/jama.2016.12260 Ko , T.-M., Tsai, C.-Y., Chen, S.-Y., Chen, K.-S., Yu, K.-H., Chu, C.-S., Huang, C.-M., Wang, C.-R., Weng, C.-T., Yu, C.-L., Hsieh, S.-C., Tsai, J.-C., Lai, W.-T., Tsai, W.-C., Yin, G.-D., Ou , T.-T., Cheng, K.-H., Yen, J.-H., Liou , T.-L., Lin, T.-H., Chen, D.-Y., Hsiao, P.-J., Weng, M.-Y., Chen, Y.-M., Chen, Chen-Hung, Liu, M.-F., Yen, H.-W., Lee, J.-J., Kuo , M.-C., Wu, C.-C., Hung, S.-Y., Luo, S.-F., Yang, Y.-H., Chuang, H.-P., Chou, Y.-C., Liao, H.-T., Wang, C.-W., Huang, C.-L., Chang, C.-S., Lee, M.-T.M., Chen, P., Wong, C.-S., Chen, Chien-Hsiun , Wu, J.-Y., Chen, Y.-T., Shen, C.-Y., Taiwan Allopurinol-SCAR Consortium, 2015. Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study. BMJ 351, h4848. https:// doi.org /10.1136/bmj.h4848 Martin, M.A., Kroetz , D.L., 2013. Abacavir Pharmacogenetics – From Initial Reports to Standard of Care. Pharmacotherapy 33, 765–775. https:// doi.org /10.1002/phar.1278 Pian , P.M.T., Galinkin , J.L., Davis, P.J., 2017. 11 - Opioids, in: Davis, P.J., Cladis , F.P. (Eds.), Smith’s Anesthesia for Infants and Children (Ninth Edition). Elsevier, Philadelphia, pp. 219-238.e7. https:// doi.org /10.1016/B978-0-323-34125-7.00011-5 Weinshilboum , R.M., Sladek , S.L., 1980. Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am. J. Hum. Genet. 32, 651.

38. Thank You for Your attention