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![References:
1. Ozdemir V, Basile CS, Masellis M, Maglia P, Kennedy J. Pharmacogenomics and personalized
therapeutics in psychiatry. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors.
Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Williams and Wilkins;
2002. p. 495–506.
[2] Ledley FD. Can pharmacogenomics make a difference in drug development? Nat Biotechnol
1999;17:731.
[3] Lesko LJ, Woodcock J. Pharmacogenomic-guided drug development: regulatory perspective.
The Pharmacogenomics Journal 2002;2:20–4.
[4] Vaszar LT, Rosen GD, Raffin TA. Pharmacogenomics and the challenge to privacy. The
Pharmacogenomics Journal 2002;2:144–7.
[5] Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical
geneticist. Clin Genet 1999;56:247–58.
[6] Kelsoe JR. Promotor prognostication: the serotonin transporter gene and antidepressant
response. Mol Psychiatry 1996;3:475–6.
[7] Bender S, Eap CB. Very high cytochrome P4501 A2 activity and non-response to clozapine.
Arch Gen Psychiatry 1998;55:1048–50.
[8] Basile VS, Ozdemir V, Masellis M, Walker ML, Meltzer HY, Lieberman JA, et al. A functional
polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia
in schizophrenia. Mol Psychiatry 2000;5:410–7.
[9] Byerly M, Devane L. Pharmacokinetics of clozapine and risperidone: a review of recent
literature. J Clin Psychopharmacol 1996;16:177–87.
[10] Pickar D, Rubinow K. Pharmacogenomics of psychiatric disorders. Trends Pharmacol Sci
2001;22:75–83.](https://image.slidesharecdn.com/pharmacogenomics-161202075053/75/Pharmacogenomics-35-2048.jpg)
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Pharmacogenomics
- 1. Pharmacogenomics Dr.Kiran A. Kantanavar Departmentof Pharmacology KSHEMA, Mangaluru. kirankantanavar@gmail.com
- 2. Introduction “Pharmacogenetics is thestudy of the genetic basis for variation in drug response.” “Pharmacogenomics involves the study of role of genes and their variations in the molecular basis of the disease and therefore the resulting pharmacologic impact of drugs on that disease”
- 3.
- 4. Factors contributing tovariation in drug response • Diet • Age • Gender • Lifestyle • Circadian & seasonal variation • Exercise • Comorbidities • Renal and hepatic function • Genetic factors
- 5.
- 6. Genetic polymorphisms Single nucleotide polymorphisms(SNPs) •Coding, nonsynonymous CCG – Pro CAG – Gln •Coding, synonymous CCG – Pro CCA – Pro •Non coding Indels •Insertions/deletions •Copy number variations oGene duplications oLarge deletions
- 8. Adequate therapeutic response Pharmacokineticproperties • Absorption • Distribution • Metabolism • Excretion Pharmacodynamic properties • Receptors • Enzymes • Ion channels • Transporters
- 9. Genetic polymorphism indrug transport • P-Glycoprotein multidrug transporter (MDR1) • Vincristine, vinblastine, doxorubicin, daunorubicin • MDR1 – major cause for Low drug level in cells
- 10. Genetic polymorphisms indrug metabolism • CYP2D6 – Tricyclic antidepressants • Poor metabolisers – high plasma concentration – toxic effects • Rapid metabolisers – low plasma concentrations – therapeutic failure – Codeine (as analgesic) • Poor metabolisers – therapeutic failure
- 11. Genetic polymorphisms indrug metabolism • CYP2C9 – Warfarin – slow metabolism – high risk of bleeding • CYP2C19 – Clopidogrel • Loss of function alleles – decreased activation of clopidogrel
- 13. Gene product DrugsResponses affected CYP2C9 Warfarin, Tolbutamide, Phenytoin, NSAIDs Anticoagulant effect of warfarin CYP2C19 Omeprazole, clopidogrel, mephenytoin, propranolol Peptic ulcer response to omeprazole, Cardio-vascular events after clopidogrel CYP2D6 Beta blockers, codeine, antidepressants, tamoxifen antipsychotics, debrisoquine, Codeine efficacy, Tardive dyskinesia from antipsychotics CYP3A4/A5/A7 Macrolides, cyclosporine, tacrolimus, CCBs, etc Efficacy of immunosuppressive effect of tacrolimus UGT1A1 (UDP glucuronosyl transferase) Irinotecan, bilirubin Irinotecan toxicity Thiopurine methyl transferase (TPMT) Mercaptopurine, thioguanine, azathioprine Thiopurine toxicity and efficacy Dihydropyramidine dehydrogenase Fluorouracil, capacitabine 5-fluorouracil toxicity
- 14. Case study • A72 year old male with metastatic colorectal cancer was prescribed an anticancer drug Irinotican 180mg/m2, as an intravenous infusion, which was repeated every 2weeks, along with several other chemotherapeutic agents. • Liver function and renal function were normal. • Blood samples were drawn.
- 15. • After thetreatment cycle, the patient experienced very severe neutropenia and diarrhea. • Plasma levels of SN-38, the active metabolite of irinotecan, were 4fould higher than those found in most patients. • The irinotecan dose was reduced by 50%. • Plasma levels of SN-38 were lower but still more than twice normal. • However after 2nd cycle, there was no neutropenia and only grade 1 diarrhea. • CT and MRI scan showed partial response to the chemotherapy.
- 16. Case study answer •Irinotecan is metabolized to the active cytotoxic molecule SN-38, which is also responsible for toxicity. • Inactivation of SN-38 occurs via the polymorphic UGT1A1 enzyme. • Carriers of the UGT1A1*28 variant have reduced enzyme activity.
- 17. Genetic polymorphisms indrug targets • Beta adrenergic receptors – 389th position Arginine Glycine Metoprolol Marked fall in BP Moderate fall in BP
- 18. Targets & receptorsDrugs Responses affected Angiotensin converting enzyme ACE inhibitors eg: Captopril, enalapril etc Renoprotective effect, hyptension, cough Dopamine recetors (D2, D3, D4) Antipsychotics – haloperidol, clozapine, thioridazine Antipsychotic induced tardive dyskinesia, acute akathesia, hyperprolactinemia in females Ion channels (HERG, KvLQT1, Mink, MiRP1) Erythromycin, cisapride, clarithromycin, quinidine Increased risk of drug induced torsdes de pointes and QT interval Serotonin transporters Antidepressants – clomipramine, fluoxetine, paroxetine, fluoxemine Clozapine effects, 5-HT neurotransmission, antidepressant response
- 19.
- 20. Assess patient’s geneticmakeup and depending on the results use appropriate medications Identify genetic polymorphisms that are responsible for therapeutic effect or adverse effect (database) Identify genes in the drug response pathway
- 22. • Clinical pharmacogenomicsimplementation consortium (CPIC) – 2009 • Guidelines for many gene–drug pairs – HLA-B - abacavir, carbamazepine – CYP2D6 - codeine – CYP2C9, VKORC1 - warfarin – UGT1A1 - irinotecan – CYP2C19 - clopidogrel Clinical practice guidelines
- 23. Clinical practice guidelines •International Warfarin Pharmacogenetics Consortium (IWPC) – Algorithm to estimate warfarin dosing
- 24. P G S HE C A N R R E E M T E A I N C C I O N G
- 25. Pharmacogenitic screening Direct sequencing •Gene of interest • Easy • Cost is less Whole genome sequencing • One time procedure for an individual • Can be stored in genetic library and information can be used whenever necessary • Polymorphism in all genes can be identified
- 26. Pharmacogenitic screening tests AmpliChipCYP450 Detects polymorphism in drug metabolizing enzymes (DMEs) such as CYP2D6, CYP2C19 Affymetrix DMET Detects polymorphism in DMEs – CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 A5 & A7 and transporters PHARMAChip Detects polymorphisms in CYP450 enzymes and in genes that code for drug receptors, transporters and other targets Therascreen Kit For use of afatinib in non-small-cell lung cancer Cobas EGFR Mutation Test For use of erlotinib in non-small-cell lung cancer
- 27. Case study • Thepatient is a 65 year old widowed white female who presented complaining of “doctors not doing their job to fix me.” • Psychiatric history: diagnosis from prior psychiatrists include Major depressive disorder (recurrent, severe), Dysthymic disorder, Personality disorder NOS and Narcissistic personality disorder. • Medical history: essential hypertension and hypercholesterolemia
- 28. • Previous medicationtrials: she has tried many psychotropic medications in the past such as fluoxetine (Prozac®), escitalopram (Lexapro®), nortriptyline (Pamelor®) and bupropion (Wellbutrin®) as monotherapy in addition to a few augmentation strategies such as adding aripiprazole (Abilify®) and quetiapine (Seroquel®) • Medications at the time of GeneSight testing: nortriptyline (Pamelor®) 50 mg PO QHS, aripiprazole (Abilify®) 5 mg PO QHS, atorvastatin (Lipitor®) 20 mg PO QHS, and lisinopril (Zestril®) 20 mg PO QAM.
- 33. Conclusions • Individualized medicinebased on personal genotypes remains a glimpse at the future. • It will not be long before the personalized information provided through genetic databases is applied to the mainstream of the health care system. • High cost and Ethical concerns for privacy - major challenges. • Constructive efforts from scientists, clinicians, ethicists and heath care managers can bring change in the lives of patients.
- 34. For more discussionon pharmacogenomics Contact – kirankantanavar@gmail.com
- 35. References: 1. Ozdemir V,Basile CS, Masellis M, Maglia P, Kennedy J. Pharmacogenomics and personalized therapeutics in psychiatry. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Williams and Wilkins; 2002. p. 495–506. [2] Ledley FD. Can pharmacogenomics make a difference in drug development? Nat Biotechnol 1999;17:731. [3] Lesko LJ, Woodcock J. Pharmacogenomic-guided drug development: regulatory perspective. The Pharmacogenomics Journal 2002;2:20–4. [4] Vaszar LT, Rosen GD, Raffin TA. Pharmacogenomics and the challenge to privacy. The Pharmacogenomics Journal 2002;2:144–7. [5] Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist. Clin Genet 1999;56:247–58. [6] Kelsoe JR. Promotor prognostication: the serotonin transporter gene and antidepressant response. Mol Psychiatry 1996;3:475–6. [7] Bender S, Eap CB. Very high cytochrome P4501 A2 activity and non-response to clozapine. Arch Gen Psychiatry 1998;55:1048–50. [8] Basile VS, Ozdemir V, Masellis M, Walker ML, Meltzer HY, Lieberman JA, et al. A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia. Mol Psychiatry 2000;5:410–7. [9] Byerly M, Devane L. Pharmacokinetics of clozapine and risperidone: a review of recent literature. J Clin Psychopharmacol 1996;16:177–87. [10] Pickar D, Rubinow K. Pharmacogenomics of psychiatric disorders. Trends Pharmacol Sci 2001;22:75–83.
Editor's Notes
- #17 Topoisomerase 1 inhibitor Analogue of Camptothecin UGT1A1 : UDP glucuronosyl transferase 1