Introduction to pharmacogenomics and personalised medicine

1. Introduction to pharmacogenomics and personalised medicine Jerzy Jankowski, MD Department of Clinical Pharmacology

2. www.zfk.ump.edu.pl

3. The Relationship Between Dose and Effect

4. Pharmacotherapy – clinical problemsAdverse Drug Reactions (ADRs) • 56% of drugs that cause ADRs are metabolized by polymorphic phase I enzymes, of which 86% are CYP P450; • only 20% of drugs associated with ADRs are substrates for non-polymorphic enzymes • ADRs cause > 100 000 deaths/y in the USA • Up to 7% of all hospital admissions in the UK and Sweden are due to ADRs • ADRs cost the US society ~US$ 100 billion

5. Pharmacotherapy – clinical problemsEfficacy • 30-60% of subjects treated with drugs do not respond to drug therapy

6. Pharmacogenomics Is the study of how an individual’s genetic makeup affects the body’s response to drugs. The key to creating personalised drugs with greater efficacy and safety Combines traditional pharmaceutical sciences with an understanding of common DNA variations in the human genome The most common DNA variations- SNPs

7. Genetic polymorphisms Exist in a human population when allelic variants occure with a frequency of 1% or greater

8. TYPES OF GENETIC VARIANTS • single nucleotide polymorphisms ( SNPs ) 1 SNP every 300 – 1000 base pairs • Insertions/deletions ( INDELS ) in comparison with SNPs, indels are much less frequent, especially in coding regions of genes • Copy number variations ( CNVs ) – large segments of DNA ( gene duplications, gene deletions, gene inversions )

10. SINGLE NUCLEOTIDE POLYMORPHISM • SNPs in the coding region cSNPs: - non-synonymous or missense (protein strucutre, stability, substrate affinty or introduce a stop codon) - synonymous or sense (transcript stability, splicing) • Noncoding SNPs may occur in 3´ and 5´ UTR, in promoter or enhancer regions, in introns or in intergenic regions

11. MOLECULAR MECHANISMS OF GENETIC POLYMORPHISMS

12. ETHNIC DIVERSITY • Polymorphisms differ in their frequencies within human populations • Polymorphisms are classified as: - cosmopolitan ( present in all ethnic group ) - population specific ( or ethnic and race ) • The presence of ethnic and race - specific polymorphisms are consistent with geographical isolation of human populations

13. Pharmacogenomics SNPs are often linked to an individual’s response to a drug.

14. Anticipated benefits of pharmacogenomics • More powerful medicine Drugs more targeted to specific diseases, maximising therapeutic effects while decreasing damage to nerby healthy cells • Better, safer drugs the First Time The best available drug therapy from the beginning; shorter recovery time; the likelikehood of adverse reactions is eliminated

15. Anticipated benefits of pharmacogenomics • More accurate methods of determinig appropriate drug dosages Current methods of basing dosages on weight and age will be replaced with dosages based on person’s genetics • Advanced screening for disease Treatments can be introduced at the most appropriate stage to maximize their therapy

16. Anticipated benefits of pharmacogenomics • Better vaccines Made of either DNA or RNA, promise all the benefits of existing vaccines without all the risks • Improvements in the drug discovery and approval process The cost and risk of clinical trials will be reduced by targeting only those persons capable of responding to a drug • Decrease in the overall cost of health care

17. The fate of a drug in the body Is affected by: Liberation Absorption Distribution Metabolism Excretion LADME

18. PHASE I AND PHASE II REACTIONS IN DRUG DYSPOSITION

19. Pathways of drug metabolism • Phase I reactions: oxidation reduction hydrolysis • Phase II reactions: glucuronidiation sulfation acetylation methylation

20. PHASE I REACTIONS convert the parent drug to a more polar (water-soluble) and/ or more reactive product by unmasking or inserting a polar group such as -OH, -SH, -NH2

21. PHASE II REACTIONS increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, sulfate, acete, glutathione, glycine and methyl groups

22. Both types of reaction convert relatively lipid- soluble original drug molecules into more water-soluble metabolites that are more easily excreted.

24. biological: gender age renal and liver fun. disease- related fac. lifestyle: smoking alkohol consumtion diet drug -drug interaction inherited Determinants of drug biotransformation

25. GENETIC CONTRIBUTION TO PK PARAMITERS 75 – 85%

26. Determinants of drug biotransformation • The potential risk factors of drug inefficacy and toxicity • Differences in drug metabolism can lead to severe toxicity or therapeutic failure

27. Determinants of drug biotransformation Of greater importance are inherited determinants that affect the kinetics and dynamics of numerous drugs.

28. Pharmacokinetic variability Refers to variability in delivery of drug to, or removal from, key molecular sits of action that mediate efficacy and/or toxicity. Drug- metabolising enzymes (DMEs) and drug transportes (P-gp) are involved in this processes.

29. Pharmacodynamic variability refers to variable drug effects despite equivalent drug delivery to molecular sits of action. This may reflect variability in the function of the drug targets (receptors or enzymes)

30. Genetic variation in genes for DMEs, drug receptors (DR) and drug transportes (DT) is associated with variability in efficacy and toxicity of drugs

31. The fate of drug in the body • The majority of pharmacogenomic differences represent variability in drug metabolism • Most of the remaining represent alternations in: • Receptors • Transporters • Protein binding • Pharmacogenetic differences in absorption or excrition of drugs are relatively uncommon

32. Polygenic Determinants of Drug Effects

33. The phenotypes of drug metabolism • The extensive metabolizer(EM) (dominant trait; inherited as either homozygous or heterozygous for the wild- type allele (wt) • The poor metabolizer(PM) recessive autosomal trait due to mutation and/or deletion of both allels; inherited as either homozygous or heterozygous for mutant allele • The ultra- extensive metabolizer (UEM) recessive autosomal trait due to gene amplification

34. Metabolism of Debrisoquin

35. Cytochrome P450 (CYP450) enzymes • The most important enzymatic system • Biosynthesis and degradation of endogenous compounds (steroids, lipids, vitamines) • Degradation of exogenous compounds (diet, environment, medications) • Highly polymorphic

36. Clasiffication of CYP450 enzymes • Amino acid similarities • Designated by a family number, a subfamily letter, a number of an individual enzyme within the subfamily and an asterisk followed by a number and a letter for each genetic (allelic) variant • www.imm.ki.se/CYPalleles/

37. CYP 450 ENZYMES

38. Cytochrome P450 (CYP450) enzymes • 57 CYP450 genes • CYP1, CYP2, CYP3 families appear to contribute to the metabolism of drugs • These CYP enzymes are involved in approximately 80% of oxidative drug metabolism and account for 50% of the overall elimination of commonly used drugs

39. Cytochrom P450 3A (CYP 3A) • 3A4, 3A5, 3A7 and 3A43 isoenzymes in adults • Chromosom 7q22.1 • Probably the most important of all DMEs • Aboundant in intestinal epithelium and in the liver • 50% of the CYP450 activity in the liver • Involved in the metabolism of more then half drugs that undergo oxidation

41. Drug interactions involving inhibition of CYP 3A

42. Drug interactions involving inhibition of CYP 3A • The interaction between grapefruit juice nad CYP 3A substrates • 250ml of this juice inhibits intestinal CYP 3A for 24- 48h. • Grapefruit juice is contraindicated when drugs extensively metabolised by CYP 3A are used • CYP 3A inhibition is reversible 2-3 days

43. Drug interactions involving inhibition of CYP 3A • The problem of drug interactions can be serious • For exapmle: interaction of erythromycin and inhibitory drugs (nitroimidazole, diltiazem, verapamil, troleandomycin) • When an orally administered drug undergoes extensive first-pass metabolism, its bioavailability in the face of CYP3A inhibition may increase severalfold, thus prolonging the presence of the drug in the body

45. Cytochrom P450 3A (CYP 3A) • Activity vary markedly among individuals of a given population • Multiple genes are involved in its regulation • Activity modulated by several factors including drugs • Drug interactions may increase or reduce CYP 3A activity (expanding the range of variablility to about 400-fold)

46. Cytochrom P450 3A (CYP 3A) • Variability in drug levels of this magnitude, potentially presents a major therapeutic problem in dosage optimization. • For example: dosage of cyclosporine in patiens receiving also ketoconazole • For example: dosage of cyclosporine in patients receiving also rifampin

48. Drug interactions involving induction of CYP 3A • The induction of CYP 3A significantlly decreases (up to 95%) the plasma levels of certain drugs administered concurrently • CYP 3A activity is especially sesnitive to modulation • Previously effective drug dosages become ineffective

50. Drug interactions involving induction of CYP 3A • The consequences of CYP 3A induction are not immediate • Steady- state levels are reached in 2-3 weeks • „Washing out” the induction effect also takes several weeks • Effectivnes of drug therapy is reduced