pharmacogenomics by vaiibhavi

Pharmacogenomics deals with the influence of genetic variation on drug response by co-relating gene expression or polymorphism with a drug’s efficacy or toxicity.

1. Pharmacogenomics

2. REVIEW ON “PHARMACOGENOMICS” Project work submitted by Miss. VAIBHAVI M. JANGDE Under the guidance of Mrs. MADHURI GITE Asst. Prof. (M. Pharm in QA) SHRI R. D. BHAKT COLLEGE OF PHARMACY, JALNA

3. Introduction Pharmacogenomics deals with the influence of genetic variation on drug response by co-relating gene expression or polymorphism with a drug’s efficacy or toxicity. It intends to identify individuals who are either more likely or less likely to respond to a drug, as well as those who require altered dose of certain drugs.

4. PHARMACOGENOMICS Benefits for patients include better drug selection for initial treatment and more accurate dosing. Benefits for drug companies include genetic targeting of clinical trials for specific groups

5. Example : Clopidogrel (Plavix) Prodrug Drug Inactive drug enzyme A enzyme I Taken by about 40 million people in the world to prevent blood clotting. CYP2C19 is responsible for its metabolic activation (see enzyme A in the diagram above). At least one loss-of-function allele is carried by 24% of the w hite non-Hispanic population, 18% of Mexicans, 33% of African Americans, and 50% of Asians. Homozygous carriers, who are poor CYP2C19 metabolizers, make up 3% to 4% of the population .

6. PERSONALISED MEDICINE There is an emerging goal among ‘translational scientists’ to make medical practice more personalized Pharmacogenetics is an important step towards that goal The effects of this movement are seen in many aspects of society

7. Polymorphisms in Pharmacogenomics Genetic variations that are common (occurring in at least 1% of the population) are known as polymorphisms , and mutations of a single nucleotide are known as single nucleotide polymorphisms (SNPs) .More than one-third of human genes have been found to be polymorphic .

8. A change in the nucleotide sequence of a gene can lead to a change in the amino acid sequence of the protein that leads to altered enzymatic activity, protein stability, and binding affinities Genetic variation thus affects drug efficacy of drugs when mutations occur in proteins that are drug targets (e.g., receptors), or are involved in drug transport mechanisms (e.g. ion channels) and safety when drug-metabolizing enzymes are involved.

9. SNPs are the most commonly occurring genetic differences. ACGCCTTGACGA A GCTTAC ACGCCTTGACGA T GCTTAC SNPs are single base pair positions in genomic DNA at which different sequence alternatives (alleles) exist wherein the least frequent allele has an abundance of 1% or greater.

10. Pharmacogenomics and Pharmacogenomics Pharmacogenetics is often a study of the variations in a targeted gene, or group of functionally related genes. Pharmacogenomics is the use of genetic information to guide the choice of drug and dose on an individual basis . Pharmacogenomics includes Pharmacogenetics

11. History

12. “ It is more important to know what sort of person has a disease than to know what sort of disease a person has.” -Hippocrates ( 460 BC – 370 BC )

13. Genetic polymorphisms in Pharmacogenomics

14. Pharmacogenomics & Drug Development Phase I studies Explain outliers or patient-to-patient variability in PK Exclude or include specific patients Normalize genotype frequencies Bridge to other populations 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 Identify genetic markers associated with clinical outcomes

15. Dose determination Phase I clinical trials (safety) 20 to 80 healthy volunteers Determine max tolerable dose Phase II clinical trials (efficacy) Several hundred patients estimate therapeutic dose range Drugs approved with a specific indication and dose range Phase III monitoring. Dose that patients actually receive depends on… Prior treatment history of patient (drug naïve?) Physicians experience with prescribing drug Empirical knowledge of appropriate dose In practice – start low, ramp to ~80% of recommended dose before trying different drug Liability issues No clinical trials are done to study dose escalation Therapeutic drug monitoring

16. Clinical Implementation of Pharmacogenomics: A Focus on Guidelines

17. APPLICATION “ Nearly one fourth of all outpatients received one or more drugs that have pharmacogenomic information in the label for that drug. The incorporation and appropriate use of pharmacogenomic information in drug labels should be tested for its ability to improve drug use and safety in the United States. ” See the FDA Pharmacogenomic Biomarkers in Drug labels for a list of drugs and their associated genetic biomarkers

18. GOALS Dosage and drug specific to individual Get it right first time Create individual metabolic profile Screen presymptomatic carriers preimplantation , prenatal, newborn disease susceptibility

19. EXAMPLES OF ADR Phenylthiourea non-taster phenotype P-glycoprotein transporter variation Aldehyde dehydrogenase CYP2C19 and omeprazole & diazepam Dihydropyridine dehydrogenase and 5-FU UDP glucuronyl transferase 1A1 and bilirubin N-acetylation polymorphism and INH (for TB) NO- sythetase and vascular tone variation…

20. Gene-Drug FDA examples HLA-B *1501 and 1502 alleles hypersensitivity responses which can lead to a rash and skin reactions that may become serious and life-threatening abacavir ( Ziagen ), carbamezepine ( Carbatrol , Tegretol ) CYP2D6 *3, *4, *5, *6, *10, *17 and *29 alleles confer "poor metabolism ” tamoxifen ( Novaldex ); CYP forms appear to predict poorer prognosis for long term survival fluoxetine (Prozac) and atomoxetine (Strattera) VKORC1 A/A and A/B haplotypes and CYP2C9 *2 and *3 alleles interactions at the target site and the removal from the body warfarin (Coumadin ) Patients with combinations of these alleles can experience elevated INR measures and increased risk of dangerous bleeding events

21. Barriers Complexity – there are millions of SNPs finding gene variations that affect drug response Which genes affect drug response? Disincentive for companies $$ for small population Disincentives for drug companies to make multiple pharmacogenomic products Educating physicians in genetics Complexity of Limited drug alternatives Fear of discrimination based on genetic test results

22. REFERENCES WEB LINKS: http ://www.pharmgkb.org/ http://pharmacogenomics.ucsd.edu http://www.phgfoundation.org/tutorials/pharmacogenomics/index.html

23. THANK YOU