Pharmacogenetics and Pharmacogenomics

Pharmacogenetics and Pharmacogenomics

1. Biol 601 Seminar May 10, 2012 Raul Soto Adam Gainford Greg Stanger The Role of Pharmacogenetics / Pharmacogenomics in Drug Development and Regulatory Review http:// www.liv.ac.uk/pharmacogenetics/dna_and_pills.jpg

2. “Different [drugs] to different patients, for the sweet ones do not benefit everyone, nor do the astringent ones, nor are all the patients able to drink the same things.” – Diseases III Hippocrates , father of Western Medicine, 2500 years ago We’ve known for a long time that not all substances have the same effects on all patients With the development of molecular genetics, now we can begin to explore WHY http://www.sculpturegallery.com/two/hippocrates5.jpg

3. Overall Scope How DNA-based differences affect PK and PD of medications How pharmacogenomics info is applied and reviewed in IND, and NDA/BLA submissions Critical issues in regulatory review Labeling implications http://3.bp.blogspot.com/_9zrxRkzw1zg/R02H0bBqiDI/AAAAAAAAAAM/Hj1YxWsZ3sg/S269/pharmacogenetics.jpg

4. Definitions Pharmacogenetics : the convergence of pharmacology and genetics, deals with genetically determined responses to drugs … also concerned with the differences in the metabolism of medications among children, adults, and senior citizens; men and women; and people with various medical conditions. Source: MedicineNet , www.medterms.com/script/main/art.asp?articlekey=4858 Pharmacogenomics : biotechnological science that combines techniques from medicine, pharmacology, and genomics; and is concerned with developing drug therapies to compensate for genetic differences in patients which cause varied responses to a single therapeutic regimen. Patient-drug interactions is a complex trait influenced by many genes. Source: www.pharmainfo.net/reviews/role-pharmacogenomics-drug-development http://www.cognigencorp.com/index.php/cognigen/our_services/

5. Definitions Pharmacokinetics : The process by which a drug is A bsorbed, D istributed, M etabolized, and E liminated ( ADME ) by the body. Source: http://medical-dictionary.thefreedictionary.com/pharmacokinetics Pharmacodynamics : The study of how a drug acts on a living organism, including the pharmacologic response and the duration and magnitude of response observed relative to the concentration of the drug at an active site in the organism . Source: http://medical-dictionary.thefreedictionary.com/pharmacodynamics PK: what the organism does to the drug PD: what the drug does to the organism

6. Variability in Drug Response People’s responses to a drug substance may vary according to various intrinsic and extrinsic factors Intrinsic: Age Gender Ethnicity Disease State (i.e. diabetes, heart disease) Organ dysfunctions (i.e. liver or kidney diseases) Physiological states (i.e. pregnancy, lactation) Genetics Extrinsic : Smoking Diet Medications a person is taking What do these have in common? Differences in the levels and patterns of gene expression http://www.getfreeimage.com/pictures/different-people-groups-pic.jpg

7. Polymorphisms Type Effects Changes in a gene’s protein coding region Δ in translated amino acid sequence => Δ protein structure, conformation => Δ protein function Changes in a gene’s promoter /regulatory regions Δ in protein expression levels Changes in # of copies of a gene Δ in protein expression levels If gene codes for a transcription factor Δ in protein expression for multiple genes If gene codes for an intron / exon splicing enzyme Δ in protein structure/function for multiple proteins Deleted / inactivated gene No protein expression, protein is absent If gene codes for metabolism-related proteins Δ in way drugs are absorbed , distributed , metabolized , excreted ; Δ in duration and intensity of effect; Δ in toxicity … Polymorphisms in enzymes, receptors, transporters, signaling proteins, etc. may affect a drug’s PK/ PD profile NOT limited to a drug’s target!

8. http://www.pharmainfo.net/reviews/role-pharmacogenomics-drug-development

9. http://mostgene.org/2009_conference/personalized_meds_Gettig.pdf

10. Examples Women have better response to serotonin reuptake inhibitor antidepressants (SSRIs) like Prozac and Paxil, than to tricyclic antidepressants like Elavil and Tofranil ; also more likely to develop depression due to low serotonin levels. Some anti-anxiety medications have better effect on men than women. Women have better response to narcotic pain relievers than to non-narcotics. Carvedilol ( Coreg ), a beta-adrenergic blocking agent used to lower blood pressure, is more effective in Africans than Caucasians. Enalopril ( Vasotec ), an angiotensin II inhibitor to lower blood pressure, is more effective in Caucasians than Africans. Heart failure combined treatment with hydralazine + isosorbine is more effective in Africans than Caucasians. Expression of high levels of alcohol dehydrogenase enzyme in Asians (85%) vs Caucasians (Swiss 20%, British 10%); alcohol is metabolized faster, causes slow heartbeat, facial flushing.

11. Real life implications … 1980-1999 study of 354 drugs… 21 % required dose changes … 79 % of those changes were safety-related dose reductions Many changes based on new info obtained AFTER drug market release Usually dose recommendations for specific populations, i.e. Renal / hepatic impairment Concomitant medications Pregnancy Drug manufacturers should have dosing recommendations for individuals with intrinsic /extrinsic factors BEFORE market release to AVOID risks of Adverse Drug Reactions (ADR).

12. Adverse Drug Reactions (ADRs) 5 % hospital admissions 10% hospitalized patients experience them 106,000 deaths and 2.2 million serious events caused by adverse drug reactions (ADRs) in the US each year ( Lazarou 1998) Jason Lazarou , MSc ; Bruce H. Pomeranz , MD, PhD; Paul N. Corey, PhD. Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies. JAMA.1998;279(15):1200-1205 4 th – 6 th leading cause of death in the US for hospitalized patients May lead to drug being withdrawn from the market http://www.scientificamerican.com/article.cfm?id=a-biochemical-way-to-reduce

13. Drugs withdrawn from the US market

14. ADRs vs polymorphisms Many metabolic enzymes are polymorphic => Evolutionary defense process 7 – 22 % of a sample of randomly selected drugs are substrates for polymorphic enzymes 59 % of drugs that cause ADRs are metabolized by polymorphic enzymes http://media.rbi.com.au/AD_Media_Library/Fluvax.jpg

15. http://ridb.kanazawa-u.ac.jp/file/image_002253.jpg

16. Metabolizing enzymes and transporters Phase I metabolizing enzymes Cytochromes P450 Phase II metabolizing enzymes UGTs, GSTs, SULTs, MTs, EHs, NATs Drug transporters Influx transporters : PGP s Efflux transporters : OATP s (organic anion transport proteins), OCTP s (organic cation transport proteins). Drug receptors Class 1 receptors : ligand -controlled ion channels Class 2 receptors : G-protein coupled receptors Receptors regulating gene expression G-proteins i.e. GNAS1, GNB3 Genetic Variations can influence the activity of, or have an effect on the expression of, the following types of proteins

17. Drug Metabolism : pathways Body uses enzymes to modify drug substances Rate of this process is relevant to duration and intensity of a drug’s pharmacological action Phase I : non-synthetic reactions Oxidation, reduction, hydrolisis , cyclization , decyclization Activate / deactivate substances Phase 2 : conjugation reactions Typically detoxify / deactivate substances Methylation , sulphation , acetylation . glucuronidation , glutathione conjugation, glycine conjugation Interference (induction, suppression, inhibition) with these processes accounts for the most common and potentially severe ADRs.

18. Drug Metabolism: sites LIVER : principal site of drug metabolism Smooth endoplasmic reticulum of liver cells OTHERS : most tissue has some metabolic capabilities Epithelial cells of gastrointestinal tract, skin, lung, kidneys http://www.doctorfungus.org/thedrugs/images/antifung_1.jpg

19. CYPs Cytochrome P450 superfamily of polymorphic enzymes Found all over the body Catalyze most Phase I oxidative reactions Major enzymatic activity occurs in hepatic CYPs ( liver ) Also expressed in the brain, lungs, kidneys, intestines, monocytes , macrophages, lymphocytes… Relevant in the bioactivation and metabolism of 75% of drugs http://www.p.chiba-u.ac.jp/lab/bukka/cyp2c9.png

20. CYP Nomenclature Families: 17 families in humans Subfamilies: 42 sub-families in humans Enzyme/gene: 55 genes and 29 pseudogenes in humans http://www.doctorfungus.org/thedrugs/images/antifung_2.gif

21. Approximately 95% of all drug oxidation in humans is the action of SIX CYP enzymes

22. Crestor ™ Member of a class of molecules called statins Used to treat high cholesterol and related conditions caused by dyslipidemia (abnormal elevation of lipids in blood Approved by FDA in August 2003 in 10mg, 20mg, and 40mg presentations 5 mg presentation was later developed for Japan

23. X-fold changes in AUC for various population groups AUC : area under the plasma concentration curve AUC for Crestor ™ varies depending on several factors : Ethnicity (esp. Japanese, Singapore ethnic Chinese) Hepatic impairment Renal impairment Person taking cyclosporine, gemfibrozil , itraconazole

24. “Because Asians appear to process the drug differently , half the standard dose can have the same cholesterol-lowering benefit in those patients, though a full dose could increase the risk of side-effects …” http://articles.latimes.com/2005/mar/03/nation/na-crestor3

25. Pharmacogenetics information was reflected in the CRESTOR ™ product label

26. Variability in Drug Response Variability in drug response and factors that contribute to it must be investigated during the drug development process Companies should submit to regulatory agencies data for key PK/PD parameters as part of the drug IND, and NDA/BLA reviews. AUC : Area under the plasma concentration curve Cmax : maximum plasma concentration Phase III clinical trials should include how these parameters vary in various population groups This information should be included in the drug’s label

27. Changes in PK/PD parameters Efficacy / safety Labeling of other drugs in the same pharmacological class Intrinsic factors Extrinsic factors Drug R & D Patients Drug labeling recommendations

28. Applications in Drug Development CYP2D6 is commonly used polymorphic enzyme to test drug metabolizing. It is becoming increasingly more common for submissions to use genotyping vs. phenotyping Distribution of submissions from 1992-2001 evaluating polymorphic enzymes

29. What do the Applications of Pharmacogenomics/PG have as goals? PK differences in different phenotypes and genotypes Use genotypes as a covariant for PK/PD in clinical trial analysis Explain outliers in PK/PD in clinical trials Sort subjects into genotypic categories by clinical effectiveness Determine if ADR is relative to certain genotypes

30. What is to come for future applications? More genotypic analysis and evaluations Investigation of multiple enzyme and transporters and receptors Genomic Analysis examples

31. Type of genomic data for drug development Alleles in different races and ethnic groups for dose-response must be considered

32. New FDA guidelines based on purpose of evaluations and the validity of biomarkers used. Need to submit new drug applications when using metabolizing enzyme biomarkers. Table 2.5

33. Altered Drug Responses and Interactions Can be caused by dietary supplements or other drugs. These interactions may be impacted by genotypes Has begun to appear in product labels

34. Voluntary vs. Required Submission of Genomic Data Regulations and guidelines Dictate what data needs to be shared with the regulating agencies and in what form Heavily regulated clinical trial environment VGDS  VXDS Voluntary Genomic Data Submission IPRG review

35. Why The Data Regulations? At any given time, there are thousands of clinical trials underway. A standard must be set to ensure consistency in the analysis of: Efficacy Variability Drug use and administration Patient screening Data quality Adverse Effects …and any other characteristic of the drug development process Access to pharmacogenomic data (VGDS) May lead to a large database of genomic data for research and optimization purposes

36. How to Present the Data The possible outcomes for data submission: Full Study Reports Contains all clinical and pharmacological data that may contribute to the evaluation of effectiveness for the proposed indication along with any information stated in the label Abbreviated Report Does not involve the effectiveness or pharmacology. Contains all of the safety information that would be found in the full study report Synopsis Format allowing the reviewer to successfully evaluate the safety data

37. Submission Guidelines for IND Data Is the data used for clinical or preclinical decisions? Used to support the drug description? Was the data collected through the detection of a known valid biomarker? * Known valid biomarker – one that is accepted by the scientific community at-large to predict a clinical outcome

38. Submission Guidelines for NDA/BLA data Will the data be used towards approval or labeling justification? Was the data collected through the detection of a known or probable biomarker? * Probable valid biomarker – Appears to have predictive value but not yet replicated or widely accepted

39. Examples… (Book gives four) 2 3 4 Stage: IND Situation: The NME is metabolized by CYP2C19. The patients genotypes are screened for CYP2C19 to determine drug dosing. Data submission format: Full Report Reasoning: Data used to support scientific arguments based on drug dosing selection Stage: Phase III Situation: The NME is metabolized by CYP2D6. After the testing occurred, a subset of patients were screened genotypically for CYP2D6 to analyze any genotype and dosing association. Data submission format: Full Report Reasoning: This data will be used for proposed labeling. Stage: Phase III Situation: The NME is metabolized by CYP2D6. After trial completion, a subset of patients were screened genotypically for CYP2D6 to find an association between plasma clearance values and genotype. Not used for labeling. Data submission format: Abbreviated Report Reasoning: Not used for label or drug description Stage: Drug Interaction Study Situation: The NME is metabolized by CYP3A. The patients genotypes are screened for CYP3A5, a polymorphism to determine its effect on inter-individual variability. Data submission format: Synopsis only required for NDA/BLA. A VGDS is recommended for NDA/BLA/IND. Reasoning: Data used to support scientific arguments based on drug dosing selection

40. Voluntary Genomic Data Submission * Regardless of data influence on drug efficacy, safety or labeling, a VGDS is recommended for all pharmacogenomic data Goal: Better collaboration between sponsors and FDA for PG data The education of physicians, healthcare management and the patient * IPRG – Agency wide review group that reviews VGDS and works on providing public and industry knowledge

41. Pharmacogenetic Labeling * Regulated by 21 CFR 201.56 PG data can be included in the following label sections: Indications and Usage Dosage and Administration Contraindications Warnings and Precautions Adverse Reactions Drug Interactions Use in Specific Populations

42. Drug Label Section Description Herceptin Indications and Usage Should be used in patients whose tumors were evaluated with a HER2 predicting assay. Purinethol Warnings / Dosage and Administration Those homozygous for TPMT defect gene may be sensitive to myelosuppressive effects and rapid bone marrow suppression. Mellaril Contraindications 7% of the normal population have a genetic defect leading to reduced activity of P450 2D6. This leads to contraindication. Examples of PG Labeling Depending on the risk/benefit, the information can be placed in multiple label sections.

43. A few IF THEN statements… IF: Genomic testing must occur prior to dosing Dose is dependent on the genotype Serious Adverse Events due to PG profile THEN: The information goes to the Indications and Usage sections The information goes to the Dosage and Administration / Warnings sections The information goes to the Contraindications section

44. Conclusion Pharmacogenomic data can greatly help us to understand the variability in drug response from person to person This will in turn lead to improved safety and efficacy during the drug development process The FDA is taking an active role for the integration of pharmacogenomic data in the drug development process. The VGDS (now VXDS) allows for an industry wide compilation for the association between genomics and drug response. Drug Response Variation - Genetic differences

45. There has been a consistent rise in the amount of pharmacogenomic data labeling and the trend will increase as we further understand our genome and the many factors that effect PK and PD of drug substances The continuous creation of assays allowing for biomarker detection presents a greater possibility for personalized medicine based on genome Conclusion …