Pharmacogenetics and Pharmacogenomics

Pharmacogenetics and pharmacogenomics is an upcoming branch in therapeutics. Various pharmacogenomic tests are currently available to aid in actual clinical practice. It has shown to have promising results in personalized medicine It is my attempt to compile the basic concepts from various books, articles, and online journals. Please feel free to comment.

1. Pharmacogenetics Dr. Prashant Shukla Junior Resident Dept of Pharmacology

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3. Background 3

4. Types of Genetic Variants A polymorphism is a variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population. Two major types of sequence variation are: single nucleotide polymorphisms (SNPs) insertions/deletions ( indels ). Indels are much less frequent in the genome and are of low frequency in coding regions 4

5. SNPs 5 A  single nucleotide polymorphism (SNP) , is a variation in a  single nucleotide  that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population (e.g. >1%). 75% 23% 2% *

6. SNPs types 6 SNPs usually occur in non-coding regions more frequently than in coding regions. Non-coding SNPs in promoters/enhancers or in 5′ and 3′ untranslated regions may affect gene transcription or transcript stability

7. How does genetic variation affect drug effect? 7

8. Introduction PHARMACOGENETICS: The effect of genetic variation on drug response , including disposition (PK), safety, tolerability and efficacy (PD). PHARMACOGENOMICS: It employs the tools for surveying the entire genome to assess multigenic determinants of drug response. 8

9. Pharmacogenetics Pharmacogenomics The study of genetic basis for variability in drug response Use of genetic information to guide the choice of drug and dose on an individual basis 9

10. Importance of Pharmacogenetics “One-size-fits-all drugs” only work for about 60 % of the population at best  40 % of the population have increased risks of ADR because their genes do not do what is intended of them 10

11. Goals of Pharmacogenetics 11

12. Pharmacogenetic phenotypes Genetic variations which affects the drug response can be divided in 3 categories: Variations affecting Pharmacokinetics . Variations affecting Drug receptor/target. Disease modifying Variations. 12

13. 13 CYP450s Transferases

14. Variations affecting PK 14 Phenotypic consequences of the deficient CYP2D6 phenotype include increased risk of toxicity of antidepressants or antipsychotics ( catabolized by the enzyme) lack of analgesic effect of codeine ( anabolized by the enzyme) The ultra-rapid phenotype is associated with extremely rapid clearance and thus decreased efficacy of antidepressants.

15. CYP2D6 Debrisoquin - Sparteine oxidation type of polymorphism: AR CYP2D6 dependent oxidation of debrisoquin and other drugs impaired 15

16. CYP2C19 AR Aromatic hydroxylation of anticonvulsant mephenytoin 16 Normal “extensive metabolizers ” ( S )- mephenytoin is extensively hydroxylated by CYP2C19 before its glucuronidation and rapid excretion in the urine, whereas ( R )- mephenytoin is slowly N - demethylated to nirvanol , an active metabolite Poor metabolizers Lack of stereospecific ( S )- mephenytoin hydroxylase activity , so both ( S )- and ( R )- mephenytoin enantiomers are N - demethylated to nirvanol , which accumulates in much higher concentrations. Increase the therapeutic efficacy of omeprazole in gastric ulcer and gastroesophageal reflux diseases.

17. CYP2C9 17

18. Relative contributions of different phase II pathways 18

19. Due to mutation, there is formation of abnormal cholinesterase. The individuals fail to inactivate Suxamethonium rapidly and experience prolonged neuro - muscular blockade. Frequency: 1/3000 19 Rate of drug acetylation varied in different population as a result of balanced polymorphism. Acetylation by N acetyltransferase (NAT 2) enzyme Slow acetylators : peripheral neuropathy Fast acetylators : Hepatotoxicity ( wrt Isoniazid ) AR trait Rapidly degraded mutant enzyme and consequently deficient S - methylation of 6-MP, thioguanine , and azathioprine , required for their detoxification. High risk of thiopurine drug-induced fatal hematopoietic toxicity. Toxic side effects due to impaired drug conjugation and/or elimination ( eg , the anticancer drug irinotecan )

20. 20 GI toxicity in case of Methotrexate Responsiveness to Depression Responsiveness to Asthma Degree of lipid lowering following Statins Cardiac arrhythmias Renal Function Test

21. Polymorphism- modifying diseases MTHFR polymorphism is linked to homocysteinemia , which in turn affects thrombosis risk. These polymorphisms do not directly affect the PK or PD of prothrombotic drugs, such as glucocorticoids , estrogens, and asparaginase , but may modify the risk of the phenotypic event (thrombosis ) in the presence of the drug . Polymorphisms in ion channels ( e.g., HERG, KvLQT1, Mink, and MiRP1) increase the risk of cardiac arrhythmias , which may be accentuated in the presence of a drug that can prolong the QT interval ( e.g., macrolide antibiotics, antihistamines ). 21

22. Clinically available Pharmacogenomic tests 22

23. 23 A pharmacogenetic trait is any measurable or discernible trait associated with a drug, including enzyme activity, drug or metabolite levels in plasma or urine, effects on BP or lipid levels, and drug-induced gene expression patterns

24. METHODOLOGY 24 deCode Genetics, Navigenics , 23andMe WBCs/ Buccal cells * PharmGKB

25. HLA gene tests a) ABACAVIR & HLAB*5701 b) ANTICONVULSANTS & HLAB*1502 c) CLOZAPINE & HLA-DQ 1*0201 2. Drug metabolism related gene test a) THIOPURINE & TPMT b) 5-FLUOROURACIL (5-FU) & DPYD c) TAMOXIFEN & CYP2D6 d) IRINOTECAN & UGT1A1*28 Various type of test are 25

26. 3) Drug target related gene test a) Trastuzumab & HER 2 b) DASATINIB, IMATINIB & BCR-ABL 1 4) Combined (metabolism & target) gene test a) WARFARIN & CYP2C9 + VKORC 1 GENOTYPING 26

27. Amplichip Determine the genotype of the patient in terms of two CYP450 enzymes: 2D6 and 2C19 FDA approved the test on Dec 24, 2004. The Amplichip CYP450 test is the first FDA approved pharmacogenetic test. 27

28. Pharmacogenetics & Drug development 28

29. 29 Key players

30. Role of pharmacogenetics in drug development Can indentify new targets. For eg . a) Genome wide assessment could identify genes whose expression differentiate inflammatory process. b) A compound could be identified that can change expression of gene responsible for inflammatory process. c) That compound can serve as starting point for anti inflammatory drug development. 30

31. 2) Pharmacogenetics may identify subsets of patients who will have a very high or a very low likelihood of responding to an agent. a) So drug can be tested on selected patients will respond & low possibility of ADRs. b) This will reduce the time & cost of drug development. 3) Pharmacogenomics can identify the subset of patient with higher risk of serious adverse effect. So these patients can be avoided in trials 31

32. Pharmacogenetic data can be submitted to FDA during IND & NDA application. If pharmacogenetics studies on animals are available then pharmacogenetic tests should be included in clinical trials. During NDA application sponsor should submit the pharmacogenetic data voluntarily, intended to put on label of the drug. 32

33. Chemogenomics , or  chemical genomics , is the systematic screening of targeted chemical libraries of small molecules against individual drug target families (e.g., GPCRs, nuclear receptors,  kinases , proteases, etc.) with the ultimate goal of identification of novel drugs and drug targets. 33 Chemogenomics

34. Pharmacogenetics in clinical practice 34

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36. Three major types of evidence that should accumulate to implicate polymorphism in clinical care. Screens of tissues from individuals linking the polymorphism to a trait. Complementary preclinical studies. Multiple supportive clinical phenotype/genotype association studies. 36

37. Despite considerable research activity, pharmacogenetics are not yet widely utilized in clinical practice. Dose adjustment on the basis of renal or hepatic dysfunction can be accepted by clinician. But there is much more hesitation from clinician to adjust the dose on pharmacogenetic ground. This can be due to resistance to accept or can be due to unfamiliarity with the principles of genetics . 37

38. Another hurdle in the path of Pharmacogenetics is Genetic Discrimination. Genetic discrimination occurs if people are treated unfairly because of differences in their DNA that increase their chances of getting a certain disease. For example, a health insurer might refuse to give coverage to a woman who has a DNA difference that raises her odds of getting breast cancer . Employers also could use DNA information to decide whether to hire or fire workers. 38

39. Genetic Information Non-discrimination Act (GINA) 2008 It is a new federal law that protects Americans from being treated unfairly because of differences in their DNA that may affect their health. The new law prevents discrimination from health insurers and employers. 39

40. Advantages of pharmacogenomics To predict a patient’s response to drugs To develop “customized” prescriptions To minimize or eliminate adverse events To improve efficacy and patient compliance To improve rational drug development Pharmacogenetic test need only be conducted once during the life time. 40

41. Advantages of pharmacogenomics … To improve the accuracy of determining appropriate dosage of drugs To screen and monitor certain diseases To develop more powerful, safer vaccines To allow improvements in drug discovery and development 41

42. Barriers of Pharmacogenomics 1. Complexity of finding gene variations that affect drug response. Millions of SNPs must be identified and analyzed to determine their involvement in drug response 2. Confidentiality, privacy and the use and storage of genetic information 42

43. Barriers of Pharmacogenomics ... 3. Educating healthcare providers and patients Complicates the process of prescribing and dispensing drugs Physicians must execute an extra diagnostic step to determine which drug is best suited to each patient 43

44. Barriers of Pharmacogenomics .. 4. Disincentives for drug companies to make multiple pharmacogenomic products Most pharmaceutical companies have been successful with their “one size fits all” approach to drug development For small market- Pharmaceutical companies hundreds of millions of dollars on pharmacogenomic based drug development. 44

45. Pharmacogenomics is in early stages of development. Much of the excitement regarding the promise of human genomics hopes on the “ PERSONALIZED MEDICINE OR MAGIC BULLETS”. Reality of the added complexity of additional testing & need for interpretation of results to individualized dosing has been ignored. Pharmacogenomics & Personalized medicine 45

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47. Clinomics Clinomics  is the study of genomics data along with its associated clinical data. As personalized medicine advances, clinomics will be a bridge between basic biological data and its effect on human health. 47

48. Pharmacogenomics has great potential to optimize drug therapy. Newer molecular diagnostic test will have to be develop to detect polymorphisms. Pharmacotherapeutics decisions will soon become fundamental for diagnosing the illness & guiding the choice & dosage of medications. CONCLUSION 48

49. Scope of Pharmacogenomics 49

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51. References 51 [1] Relling MV, Giacomini KM. Pharmacogenetics Brunton Laurence, Chabner Bruce, Knollman Bjorn, editors. Goodman and Gillman’s The Pharmacological Basis of Theraputics.12ed. USA: McGraw Hills; 2011.p145-68. [2] Rang HP, Dale M M , Ritter JM, Flower RJ, Henderson G. Pharmacogenetics , Pharmacogenomics & Personalised medicine. Hyde Madelane , Mortimer Alexandra, editors. Pharmacology. 7ed.Britain: Elsevier Churchill Living stone ;2012.p132-8. [3] http://www.genome.gov/10002077#al-2 [4] http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

52. References… [5] http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126957.pdf [6] http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm116702.pdf [7] Semizarov D, Blomme D.Introduction genomics & personalised medicine.Genomics in Drug Discovery and Development .1ed. USA: Wiley; 2009.p1-24. [8] Dr. Hemant Banga’s Seminar on Pharmacogenetics 52

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