Pharmacogenomics: The Future of Personalized Medicine

1. Pharmacogenomics: The Future of Personalized Medicine Kimberly Dunbar, PA-S2 South University Khalil Khlifi, Pharm D. Candidate University of Georgia

2. Objectives • Provide an overview of genomics and its implications in medicine • Discuss the challenges of genomics • Discuss examples of “Hot Topic” genomic finds • Discuss examples of drug targeted therapeutics

3. Case Study • You are rounding on a 65 yr old Caucasian female who presented to the ER yesterday with a recent h/o loss of consciousness and fall • She is still complaining of pain and right sided weakness • She is stable at this time • Xray reveals right hip fracture • CT and MRI reveals CVA • EKG shows Atrial Fibrillation

4. What’s going on? • Proper emergency treatment was completed but she is still complaining of severe pain despite morphine • The ER physician started her on Coumadin 3mg daily and her INR is 4.0

5. What is Genomics?? • Newer branch of medicine that deals with the influence of genetic variation on drug response in patients by correlating their gene expression with a drug’s efficacy and toxicity3

6. Science of Genomics • Although the genomes of individuals are 99.9% identical, the small 0.1% accounts for a possibility of 3 million polymorphisms • These polymorphisms can account for variations in protein expression and function, resulting in phenotypes affected for disease or drug response • Mechanism of action for drug therapy depend on the molecular interaction of the drug with the specific protein target: receptors, transporters, or cell-signaling pathways • Polymorphisms in each individual’s genome accounts for the variation in drug response due to differences in the coding of their individual protein expression

7. Science of Genomics • Possible causes of polymorphisms are: • Insertion/Deletion Polymorphisms • Gene Duplications • Gene Deletions • Consequences of polymorphisms • May result in different amino acid sequences or a stop codon • May result in a change to protein function, quantity, or expression • May alter stability of mRNA • Benign

8. Pharmacogenetics vs. Pharmacogenomics • Pharmacogenetics is the study of how genetic differences in a single gene influence variability in drug response • Pharmacogenomics is the study of how genetic differences in multiple genes influence variability in drug response

9. What does it mean for patients? • Ideally, genomics would optimize drug therapy for patients based on prescribing medication that would deliver the best results based on the patient’s genotype, while minimizing the adverse effects • The theory involves better pharmaceutical outcomes for patients and possibly finding the right mix of medications for that patient, thereby reducing the need for polypharmacy in some cases

10. What does this mean to healthcare providers? • As healthcare providers, we are given the task of using the scope of genomics to tailor medication therapy to a patient that would maximize the efficacy and decrease the adverse events • Patient’s genomes would give us clues into what drug classes would work best for them and which ones would have minimal effect on their therapeutic goal outcomes

11. Polymorphisms in the Renin-Angiotensin System and Cognitive Improvement • Currently there is research being conducted to determine the efficacy on ACE inhibitors and their effect on cognition • Two polymorphisms exist within the angiotensinogen gene and ACE gene • The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) revealed that he use of ACE-I reduced the risk of cognitive impairment in those with previous history of a stroke • The Hypertension in the Very Elderly Trial revealed that there was no improvement in cognition or dementia in those treated with ACE-I

12. Angiotensin Converting Enzyme (ACE) Gene • The DD polymorphism leads to elevated levels of plasma ACE • There is only one defined polymorphism currently with this gene: • ACE-ID (Genotypes: D/D, I/D, I/I)

13. Angiotensinogen (AGT) Gene • Codes the angiotensinogen protein which is involved in the production of angiotensin II • There are two different polymorphisms present in this gene • AGTM235T (Genotypes: C/C, C/T, T/T) • AGT6 (Genotypes: A/A, A/G, G/G) • M235T polymorphism is associated with higher angiotensinogen levels and possibly higher renin angiotensin system activity

14. Results of Current Research • There seems to be some protective property against cognitive decline only in individuals who have the AA genotype of the 6AGT or CC genotype of M235T when treated with an ACE-I • Polymorphisms in the ACE-ID showed no improvement in cognition decline with treatment with ACE-I

15. “Hot Topics” • Warfarin and CYP2C9 • Genetic polymorphisms have been found that decrease the activity of the CYP2C9 metabolizing enzyme • Patients with the polymorphism require a smaller dose than those without the polymorphism because warfarin is not metabolized at the same rate for the deficient patients • Patients were at higher risk for serious or life-threatening bleeds if the polymorphism was present (Hazard Ratio of 3.94 during first e months of follow up)

16. “Hot Topics” • CYP2D6 Polymorphisms • Responsible for the metabolism of antidepressants, antipsychotics, analgesics, acetylcholinesterase inhibitors, etc • Polymorphism are classified as follows: • Ultrarapid metabolizers (UM) • Extensive Metabolizers (EM) • Intermediate Metabolizers (IM) • Poor Metabolizers (PM) • Most people are EMs (>80%) • PMs and UMs tend to show higher transaminase activity than EMs and IMs

17. “Hot Topics” • CYP2D6 Polymorphisms and antidepressants • There was an increase rate of adverse effects in the patient population of poor metabolizers • Prozac death in child attributed to CYP2D6 poor metabolizer genotype • CYP2D6 poor metabolizers with severe mental illness had more adverse drug reactions, increased cost of care, and longer hospital stays

18. “Hot Topics” • CYP2D6 Polymorphisms and Acetylcholinesterase Inhibitors • Poor metabolizers and Ultrarapid metabolizers responded poorly to Donepezil for treatment of Alzheimer’s disease • Extensive metabolizers and intermediate metabolizers improved their cognitive function by 10% and 5% of their MMSE score, respectively • While poor metabolizers and Ultrarapid metabolizers declined 13% and 6%, respectively

19. “Hot Topics” • CYP2C19 and Proton Pump Inhibitors (PPI’s) • Patients being treated with PPI’s for ulceration had variation in cure rate based on their genotype • RM- 28.6% • EM- 60% • PM- 100% • Patients with rapid or extensive metabolism were more likely to have treatment failure and decreased quality of life

20. Drug Targeted Therapies • Breast Cancer • Herceptin (Trastuzumab) • Human Epidermal Growth Factor Receptor 2 (HER-2) is over expressed in about 25-30% of breast cancers • Helps clinicians predict the performance of therapy early and with a high degree of certainty • Colorectal Cancer • Vectibix (Panitumumab) and Erbitux (Cetuximab) • KRAS mutation is predictive of a very poor response to the following targeted therapies • Patients with wild-type KRAS will typically respond to Vectibix but is not a guarantee • Patients in the Phase III CRYSTAL study with wild-type KRAS gene treated with Erbitux showed a response rate of 59% and a 32% decrease in risk of disease progression

21. Drug Targeted Therapies • Gastrointestinal Stromal Tumors (GIST) • CD117 is a proto-oncogene and overexpression can lead to cancer • Mutation of CD117 have also been implicated in leukemias, melanomas, and mast cell disease • Efficacy of Gleevec (Imatanib) is determined by the mutation status of CD117 • Mutation is exon 11 is more responsive to Gleevec, however if the mutation is on exon 17 the receptor is not inhibited by Gleevec

22. Drug Targeted Therapies • APOE (apolipoprotein E) gene is associated with increased risk for Alzheimer’s disease • APOE-4 allele correlates with a poorer prognosis and therapeutic response • 60% of APOE-4 carriers demonstrated a lower response to Tacrine than 80% of APOE-4 non-carriers • APOE-4 non-carriers have been shown to exhibit cognitive and functional improvement with rosiglitazone, whereas APOE-4 carriers showed no improvement or some decline • Better response to donepezil has been observed in APOE-4 carriers

23. Case Study • 65 year old female with refractory hip pain with morphine and elevated INR with coumadin • What polymorphisms does this patient most likely have? • What changes in her therapy should be made?

24. Answers • This patient most likely has a CYP2D6 and CYP2C9 polymorphism • The CYP2C9 polymorphism decreases her metabolic rate of coumadin, leading to a lower dose requirement for her goal INR of 2-3 • The analgesic effect of morphine is decreased in CYP2D6 polymorphisms so she will require an analgesic that is metabolized by a different enzyme, such as hydromorphone (glucuronidation)

25. Bonus Questions • If this patient was a poor metabolizer of CYP2D6 and were to develop Alzheimer’s disease, what medications would render the best response? • What medications would result in a poor response?

26. Bonus Answers • Namenda, exelon, and tacrine are metabolized by other mechanisms that are unaffected by liver insufficiency. These would result in a better therapeutic response in this patient. • Galantamine, razadyne and donepezil are metabolized in the liver by CYP2D6 and would be associated with a poor response

27. Conclusions • Therapeutic response in many disease processes is genotype-specific and multifactorial • Tailoring medication regimens based on patient genomes maximizes efficacy and compliance while avoiding adverse effects and drug-drug interactions • Personalized therapeutics is the future of medicine!

28. References • Cacabelos, Ramon. "Pharmacogenomics and Therapeutic Prospects in Dementia." Eur Arch Psychiatry Clin Neurosci 258 (2008): 28-47. PubMed. EuroEspes Biomedical Research Center. Web. 29 Jan. 2012. • Takeda, Masatoshi et al. "Pharmacogenomics of Alzheimer's Disease." Asia-Pacific Psychiatry 3 (2011): 10-16. PubMed. Osaka University Graduate School of Medicine, 7 Dec. 2010. Web. 29 Jan. 2012. • Shenfield, Gilliam M. "Genetic Polymorphisms, Drug Metabolism and Drug Concentrations."Clinical Biochem Review 25.4 (2004): 203-06. Genetic Polymorphisms, Drug Metabolism and Drug Concentrations. NCBI. Web. 25 Jan. 2012. • "Pharmacogenomics." Wikipedia, the Free Encyclopedia. 12 Dec. 2011. Web. 28 Jan. 2012. <http://en.wikipedia.org/wiki/Pharmacogenomics>. • Hajjar, Ihab, Stephen Kritchevsky, Anne B. Newman, Rongling Li, Kristine Yaffe, Eleanor M. Simonsick, and Lewis A. Lipsitz. "Renin Angiotensin System Gene Polymorphisms Modify Angiotensin-Converting Enzyme Inhibitors' Effect on Cognitive Function: The Health, Aging and Body Composition Study."Journal of the American Geriatrics Society 58.6 (2010): 1035-042. Print. • Furuta,T.et.al. Ann Intern Med 1998;129:1027-1030 • Higashi et al. “Association Between CYP2C9 Genetic Variants and Anticoagulation-Related Oucomes During Warfarin Therapy” JAMA 2002;28