[Final] Pharmacogenetics and Pharmacogenomics - WITH NOTES
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This document summarizes a seminar presentation on the role of pharmacogenetics and pharmacogenomics in drug development and regulatory review. It discusses how genetic differences can impact how individuals metabolize and respond to drugs in terms of pharmacokinetics and pharmacodynamics. Factors like ethnicity, age, organ function, and genetics were presented as influencing a drug's effects. The role of metabolizing enzymes and transporters encoded by polymorphic genes in contributing to variability in drug responses and adverse events was emphasized. The importance of considering such genetic data during clinical trials and including relevant information in drug labels to allow for personalized dosing was also stressed.
![ “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 ofWestern
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](https://image.slidesharecdn.com/dfeb8045-e44b-4a3d-ba1a-f9659be9a770-160804041710/85/Final-Pharmacogenetics-and-Pharmacogenomics-WITH-NOTES-2-320.jpg)
![[Final] Pharmacogenetics and Pharmacogenomics - WITH NOTES](https://image.slidesharecdn.com/dfeb8045-e44b-4a3d-ba1a-f9659be9a770-160804041710/85/Final-Pharmacogenetics-and-Pharmacogenomics-WITH-NOTES-13-320.jpg)
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[Final] Pharmacogenetics and Pharmacogenomics - WITH NOTES
- 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 ofWestern 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. 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/AAAAAAAAAA M/Hj1YxWsZ3sg/S269/pharmacogenetics.jpg
- 4. 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/co gnigen/our_services/
- 5. Pharmacokinetics: The process by which a drug is Absorbed, Distributed, Metabolized, and Eliminated (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. 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. 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!
- 10. 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. 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 ofAdverse Drug Reactions (ADR).
- 12. 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 4th – 6th 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
- 14. 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
- 16. Phase I metabolizing enzymes Cytochromes P450 Phase II metabolizing enzymes UGTs, GSTs, SULTs, MTs, EHs, NATs Drug transporters Influx transporters: PGPs Efflux transporters: OATPs (organic anion transport proteins), OCTPs (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 GeneticVariations can influence the activity of, or have an effect on the expression of, the following types of proteins
- 17. 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. 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. 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. Families: 17 families in humans Subfamilies: 42 sub-families in humans Enzyme/gene: 55 genes and 29 pseudogenes in humans http://www.doctorfungus.org/t hedrugs/images/antifung_2.gif
- 21. Approximately 95% of all drug oxidation in humans is the action of SIX CYP enzymes
- 22. 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. 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
- 26. 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. 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. 1. PK differences in different phenotypes and genotypes 2. Use genotypes as a covariant for PK/PD in clinical trial analysis 3. Explain outliers in PK/PD in clinical trials 4. Sort subjects into genotypic categories by clinical effectiveness 5. Determine if ADR is relative to certain genotypes
- 30. More genotypic analysis and evaluations Investigation of multiple enzyme and transporters and receptors Genomic Analysis examples
- 31. 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. Can be caused by dietary supplements or other drugs. These interactions may be impacted by genotypes Has begun to appear in product labels
- 34. 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 VoluntaryGenomic Data Submission IPRG review
- 35. 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. 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. 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. 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. (Book gives four) 1 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. AVGDS is recommended for NDA/BLA/IND. Reasoning: Data used to support scientific arguments based on drug dosing selection
- 40. * 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 reviewsVGDS and works on providing public and industry knowledge
- 41. * 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 forTPMT 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. Depending on the risk/benefit, the information can be placed in multiple label sections.
- 43. IF: 1. Genomic testing must occur prior to dosing 2. Dose is dependent on the genotype 3. Serious Adverse Events due to PG profile THEN: 1. The information goes to the Indications and Usage sections 2. The information goes to the Dosage and Administration /Warnings sections 3. The information goes to the Contraindications section
- 44. • 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. •TheVGDS (nowVXDS) allows for an industry wide compilation for the association between genomics and drug response. Drug ResponseVariation - 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
Editor's Notes
- #2: Good evening, our group members are Adam Gainford, Greg Stanger, and myself Raul Soto. We’re going to talk about the Role of Pharmacogenetics and Pharmacogenomics in Drug Development and Regulatory Review
- #3: I want to start with a quote … (read it) This is from Hippocrates, one of the great men of Ancient Greece, the father of Western Medicine We’ve known for a long time … But just NOW, with the development …
- #4: In very general terms, we will talk about … (read)
- #5: Let’s start with some definitions… Pharmacogenetics deals with how an individual’s genetic makeup affects the person’s response to drugs… differences in how drugs are metabolized based on age, gender, ethnic background, medical conditions… Pharmacogenomics deals with using knowledge from various branches of science to compensate for those differences, for example by changing doses.
- #6: Pharmacokinetics is the study of how a drug gets ABSORBED into the organism, DISTRIBUTED throughout tissues, METABOLIZED, and ultimately ELIMINATED from the organism… the typical acronym for this is ADME Pharmacodynamics is the study of how the drug acts on the body: WHAT is the EFFECT that is has, HOW INTENSE is that effect, HOW LONG does it last, any associated TOXICITY… as a function of its concentration. So in summary PK …
- #7: The SAME dose of a drug substance can have different effects on different individuals. This can be due to a series of INTRINSIC and EXTRINSIC factors Some of these factors are … (read them) What do they all have in common? All related to differences …
- #8: A bit of a review from our Genetics courses … When you have various versions of a gene, various alleles … If the change is in the coding region that MAY alter the structure and function of the protein product If it’s in the promoter region that may alter how and when the gene is expressed Etc … NOT limited to the drug’s target… So we all probably know that if we our drug targets a receptor, and there’s 4 alleles coding for 4 slightly different versions of this receptor, and our drug binds better to allele 1 and not so good to allele 4… that’s only ONE way genetic polymorphisms can affect how our drug works. Polymorphisms in metabolic enzymes that interact with our drug are ALSO incredibly important.
- #9: For some people the SAME dose of the SAME drug will be NOT toxic AND beneficial For some it will be NOT toxic but also NOT beneficial For some it will be TOXIC but also beneficial And for some it will be TOXIC AND not beneficial So, how BIG is this problem in real life… it turns out to be … VERY BIG
- #10: These are some of the most common health issues … and you can see that major drugs are just NOT EFFECTIVE for a significant percentage of the population
- #11: I won’t go into the details, these are just examples, for those of you who are interested of various substances that have different effects on different groups of people depending on gender or ethnicity.
- #12: Refer to study that found that ONE FIFTH of all people have required changes in the doses of their medication And out of those instances, almost 80% were because of SAFETY dose reductions, people having adverse events. Now these are CORRECTIVE measures, they were finding that these drugs had these negative effects on some groups AFTER the drug was released. And that is just NOT ENOUGH The take-home message here is that drug manufacturers should FIND OUT about these effects BEFORE drugs are released, to PREVENT putting the patiente at risk of an Adverse Drug Reactions
- #13: And that is because Adverse Drug Reactions are a BIG problem. 5% of all hospital admissions 10% of all hospitalized people have them OVER 100,000 deaths and over 2 MILLION people affected every year, in the USA alone. 4th – 6th leading cause of death in hospitals The key point here is that Adverse Reactions are a BIG deal. We are in this business to HELP people, NOT to send them to the hospital, or hurt them, or kill them. In some cases the FDA will order your drug removed from the market because of ADRs
- #14: Here’s a list of drugs the FDA removed from the market between 1997 and 2001 , due to adverse reactions ….
- #15: So , what’s the relationship between Adverse Reactions and polymorphisms? Many … if you take a random sample of the most commonly prescribed drugs, from 7 – 22% of them are substrates for polymorphic metabolic enzymes HOWEVER if you take the drugs that tend to cause Adverse Reactions, you will find that almost 60% of them are metabolized by polymorphic enzymes So there is a correlation there… if your drug is metabolized by a polymorphic metabolic enzyme, there’s a chance people with different versions of the enzyme will metabolize the drug differently, and SOME may get Adverse Reactions
- #16: You give the SAME dose of the SAME drug to 3 people with different versions of a metabolic enzyme. If a person is homozygous for the wild type alleles of this metabolic enzyme, they’ll take the drug, they get a therapeutic effect, stays within the safety region NOW… You get a person who is heterozygous, with a wild type allele AND a variant that works slightly different, THAT person will have a DIFFERENT response to the drug. They will still get a therapeutic effect, in fact MORE effect for the same dose than the first person, but they will ALSO get some ADVERSE drug reactions due to toxicity. So for this person a SMALLER dose of the drug would bring the desired effect and lower the risk. THEN … you get a person who is homozygous for the variant, and that person is going to have a COMPLETELY different reaction to the drug. That’s person’s liver is going to metabolize the drug in a COMPLETELY different manner … he or she will experience serious adverse side effects. THIS person probably needs a different drug.
- #17: Like I mentioned before, our drug molecule interacts with various other proteins in the body, not just the target. There are metabolizing enzymes families, there are also drug transporter protein families Polymorphisms in all these can have an effect on how the drug acts on the patient’s body
- #18: This is basically background information about how drugs are metabolized. There’s two main phases , each has different types of biochemical processes, they are mediated by different enzymes. The key point here is that the MAJORITY of Adverse reactions happen when these processes are affected in some way.
- #19: This is basic anatomy; the main site in the body where drugs are metabolized is the LIVER
- #20: There’s a very important family of metabolic enzymes called CYP They are highly polymorphic, lot of different versions They’re the main enzyme responsible for Phase I of drug metabolism in the liver They are involved in activating and metabolizing 75% of the drugs Polymorphisms in liver enzyme CYP2D6 : people with low levels of CYP2D6 will require smaller doses of many drugs, and are more at risk of adverse drug reactions.
- #21: This is the naming convention for these enzymes, I bring this so you can see… there are 17 families, 42 subfamilies, and there are over 50 genes coding for them. Run the permutations in your head… This should give you an idea of how many different CYPs there are, of the immense complexity of human metabolism However, there’s good news…
- #23: Now after seeing how pharmacogenetics may affect a person’s response to a drug, let’s take a look at a real-world case CRESTOR, from AstraZeneca, a statin, lowers bad cholesterol and increases the good one. It was originally approved by the FDA in August 2003. I was part of that launch, I worked at the AZ manufacturing site that makes Crestor, was responsible for the startup and validation of the packaging building, packaging lines. AZ initially came out with 3 presentations for Crestor, 10, 20, and 40. But LATER it was necessary to develop an additional presentation, a 5mg dose for the Japanese market. WHY?
- #24: One important parameter in Pharmacokinetics, the area under the plasma concentration curve This figure shows the X-fold increase in AUC for various groups when compared to the control group. And you can see that some people were metabolizing Crestor differently from most people… people with kidney and liver problems, people taking some specific medicines, and people from an East Asian ethnic background. And this was discovered AFTER Crestor was released to the market.
- #26: So AstraZeneca CHANGED the labeling information for Crestor, taking into account these groups that metabolize the drug differently
- #27: So, KEY TAKEAWAYS (read)
- #28: Your drug labeling info should include all of these …
- #31: http://universe-review.ca/I11-50-PCR.jpg http://www.biosci.ohio-state.edu/~plantbio/osu_pcmb/pcmb_lab_resources/images/pcmb102/biotech/restriction_digest1.jpg http://upload.wikimedia.org/wikipedia/en/thumb/d/d9/DotBlotDemo.jpg/350px-DotBlotDemo.jpg
- #32: https://encrypted-tbn0.google.com/images?q=tbn:ANd9GcR_MoE0AXc6jdEMSCwSnMBbAAKIP5dLBsCYNHjqWJ05lfg7uJGu8Q http://www.nature.com/clpt/journal/v84/n3/images/clpt2008114f1.gif