Psychopharmacogenomicsconceptual reality or awaiting dream? Dr. Swanand S Pathak MBBS MD DACM IDCR Dept. of Pharmacology JNMC, Sawangi email@example.com
Part I ( basic concepts ) What is pharmacogenomics Difference between the pharmacogenetics and pharmacogenomics. What is psychopharmacogenomics Historical aspects of pharmacogenomics What are SNPs Concept of CYP enzymes and genetics Part II ( neuropsychopharmacogenomics) Psychopharmacogenomics in relation to antideparessants , atipsyachotics and mood stabilizers. Psychopharmacogenomics in relation with the drug development in psychiatry
Variability in Drug ResponseDisease Drug Class Rate of Poor responseAsthma Beta-agonists 40-75%Hypertension Various 30%Solid Cancers Various 70%Depression SSRIs, tricyclics 20-40%Diabetes Sulfonylureas, others 50%Arthritis NSAIDs, COX-2 inhibitors 30-60%Schizophrenia Various 25-75%
( lieberman et al N Engl J Med 2005) Clinical antipsychotic trials of intervention effectiveness (CATIE) : 18 months 74% discontinued : lack of efficacy or tolerability.
Pharmacogenomics holds the promise that drugs might one day be tailor-made for individuals and adapted to each persons own genetic makeup.Environment, diet, age, lifestyle, and state of health all can influence a persons response to medicines, but understanding an individuals genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety.
Important Facts Human genome = 22 chromosome pairs and 1 pair of sex chromosomes Functional unit of the genome = gene 2% of genes code for proteins, remainder is structural for DNA Entire genome = 3 billion DNA pairs, with ~30,000 protein coding genes
Allele An allele is one member of a pair that makes up a gene 2 same alleles are homozygous (one allele on each part a pair of chromosomes) 2 different alleles are heterozygous
• DNA sequence of all human beings is 99.9% identical • Our DNAs differ by 0.1%. • Does it make a difference ? YES !0.1% difference translates into 3 millionseparate “spelling” differences in agenome of 3 billion bases
Genetic Polymorphism? A genetic polymorphism is any mutant or variant gene that occurs with a frequency of more than 1% in the normal population Denoted by : *
POLYMORPHISM TYPES SNP INSERTIONS DELETIONS• Missense • Missense • Missense• Nonsense • Nonsense • Nonsense• Frameshift • Frameshift • Frameshift Go to
PolymorphismsSingle nucleotide polymorphisms (SNP) ……..G G T A A C T T G …... ……..G G C A A C T T G …... • Most common • Incidence 1 per 300 - 600bp
Why diazepam metabolism is slower in Asians compared to Caucasians?Because Asians have high frequency of mutant alleles CYP2C19 Genotype Allele Diazepam t1/2 caucasians CYP2C19 *1/*1 20 hours FM Asians CYP2C19 *2/*2 84 hours PM
Function of P-gp The human MDR1 encodes amembrane P-glycoprotein thatmediates ATP-dependent efflux. P-gp resides in the plasma membraneand functions as an efflux transporter ofa wide variety of natural compoundsand dugs
This girl may develop side effects to Warfarin Glibenclamide Acenocoumarol Tolbutamide Losartan Ibuprofen Irbesartan Flurbiprofen Glipizde Diclofenac All metabolized by CYP2C9 enzyme
CYP2D6 Polymorphisms and Psychiatric Drug Response Increased rate of adverse effects in poor metabolizers due to increased plasma concentrations of drug: Fluoxetine (Prozac®) death in child attributed to CYP2D6 poor metabolizer genotype Side effects of antipsychotic drugs occur more frequently in CYP2D6 poor metabolizers CYP2D6 poor metabolizers with severe mental illness had more adverse drug reactions, increased cost of care, and longer hospital stays
Pharmacogenomics Information in the Published Literature Zineh I et al. Ann Pharmacother. 2006; 40: 639-44
• An investigative drug showed NO statistically significant effect when given to 400 Alzheimer’s patients,• A clinically significant response was elicited when patients were stratified according to ApoE subtype (Richard et al., 1997).
Pre-clinical Gene Expression Toxicogenomics Predict toxicity of candidate compounds Identify mechanisms of toxicity Identify potential biomarkers for toxicity or efficacy for future clinical studies
Phase I studiesExclude or include specific patientsNormalize genotype frequencies
Phase II/III studies Identify genetically-defined groups with more pronounced or rapidly progressing disease Exclude/include at-risk individuals Stratify studies based on genotypes Clinical response Risk of adverse events Where appropriate, develop drugs for specific groups
FDA and Pharmacogenomics FDA published: “Draft Guidance for Industry: Pharmacogenomic Data Submission” in 2003. (currently under revision) Set criteria for Voluntary Genomic Data Submission (VGDS) (http://www.fda.gov/cder/guidance/5900dft.pdf)
What are the anticipated benefits of Pharmacogenomics?
Individualized MedicinesPharmaceutical companies will be able tocreate drugs based on the proteins,enzymes, and RNA molecules associatedwith genes and diseases.This will facilitate drug discovery and allowdrug makers to produce a therapy moretargeted to specific diseases. This accuracynot only will maximize therapeutic effectsbut also decrease damage to nearby healthycells.
Cost Effectiveness ? • Phase III trial - CNS product -4500 patients- Cost per patients $ 8000 - $ 12,000• Eliminate 10% (Approx 450 subjects) of trial population (Non-responders) Using Pharmacogenomic Save $ 3,60,000 - $5,40,000. (Murphy , Pharmacogenetics, 2000; 10:1-7)
Some ethical IssuesCould the development of medicines forspecific groups of the population excludeothers?Will the development of unprofitable, butdesirable, medicines be neglected?Who will have access to genetic informationand databases?
Research Issues Translating• Narrower target population could exclude those who might also benefit from therapies• Evaluating therapies in smaller, targeted trials might miss critical, albeit rare, adverse drug events
Social IssuesHealth Horoscope Will I develop this disease ten years from now? • Can I indulge in unhealthy habits (e.g., smoking, junk food, not exercising, etc.) if I don’t have a particular disease susceptibility?
Patient requires Treatment Examination by the PhysicianGenomic testing Traditional investigations EXPERT SYSTEM Decision making by Physician, assisted by an Expert System (interactive interpretation) Prescribes individualized drug treatment
The Next Diagnostic Chips?Additional diagnostics are needed:General: CYP2C9; CYP3A5; CYP2B6;MDR-1; UDP Glucuronosyltransferases(UGTs);N-acetyltransferases (NATs)Oncology: thiopurine methyltransferase(TMPT);Thymidilate synthase; dihydropyrimidine
Personalized Medicine: “when?” SMART CARD In your wallet by 2025? Praveen khairkar 97236407611 GENOME Or maybe by 2050? (Confidential)Opinion: This sort of card would initially (~2025?) include mostlyinformation related to drug metabolizing enzymesAround ~2050 it might include an entire individual genome(or at least, few millions SNPs..)
Science or Science Fiction ?Unrealistic projections for 2025:Most medicines will be prescribedaccording to patient genotypingGenomics would allow full insight intothe biological basis of complex humandiseases
PGx: Science and Science FictionRealistic projections for 2025 Genotyping would allow far smaller rates of adverse reactions for most drugs In several medical disciplines, genomics would allow far better medical treatment (oncology; psychiatry; neurology)
Part I What is pharmacogenomics Difference between the pharmacogenetics and pharmacogenomics. What is psychopharmacogenomics Historical aspects of pharmacogenomics What are SNPs Concept of CYP enzymes and genetics Part II Psychopharmacogenomics in relation to antideparessants , atipsyachotics and mood stabilizers. Psycchopharmacogenomics in relation with the drug development in psychiatry
Conceptual reality or awaiting dream ? Definitely a conceptual reality For grass root patients and practitioners … there is still a long long way to go …to fulfill the dream …
Acknowledgements Dr. Praveen Khairkar Dr. Sushil Verma Dr. Aniket Shukla Dr. Adithan Google and Wikipedia