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Pharmacogenetics and Pharmacogenomics

Pharmacogenetics and Pharmacogenomics

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Pharmacogenetics and Pharmacogenomics

  1. 1. Biol 601 Seminar May 10, 2012 Raul Soto Adam Gainford Greg Stanger The Role of Pharmacogenetics / Pharmacogenomics in Drug Development and Regulatory Review
  2. 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
  3. 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 M/Hj1YxWsZ3sg/S269/pharmacogenetics.jpg
  4. 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,  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: gnigen/our_services/
  5. 5.  Pharmacokinetics: The process by which a drug is Absorbed, Distributed, Metabolized, and Eliminated (ADME) by the body.  Source:  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:  PK: what the organism does to the drug  PD: what the drug does to the organism
  6. 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
  7. 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!
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  10. 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. 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 of Adverse Drug Reactions (ADR).
  12. 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 way-to-reduce
  13. 13.  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
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  15. 15. 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
  16. 16.  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.
  17. 17.  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
  18. 18.  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
  19. 19.  Families: 17 families in humans  Subfamilies: 42 sub-families in humans  Enzyme/gene: 55 genes and 29 pseudogenes in humans hedrugs/images/antifung_2.gif
  20. 20. Approximately 95% of all drug oxidation in humans is the action of SIX CYP enzymes
  21. 21.  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
  22. 22.  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
  23. 23.  “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…”
  24. 24.  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
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28.  More genotypic analysis and evaluations  Investigation of multiple enzyme and transporters and receptors Genomic Analysis examples
  29. 29. Alleles in different races and ethnic groups for dose-response must be considered
  30. 30.  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
  31. 31.  Can be caused by dietary supplements or other drugs.  These interactions may be impacted by genotypes  Has begun to appear in product labels
  32. 32.  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
  33. 33.  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
  34. 34.  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
  35. 35. 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
  36. 36. 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
  37. 37. (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
  38. 38. * 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
  39. 39. * 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
  40. 40. 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.
  41. 41. 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
  42. 42. • 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
  43. 43. •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

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Pharmacogenetics and Pharmacogenomics


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