Biomarkers & Pharmacogenomics

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in CNS disorders. Subbu. . Apparsundaram. , PhD. CSO, V . ClinBio. subbu@vclinbio.com. +1 862 485 7489. www.vclinbio.com. Sri Ramachandra University. Porur. , Chennai, India. . omics. based prediction of drug response profiling. ID: 449195 Download Presentation

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Biomarkers & Pharmacogenomics




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Slide1

Biomarkers & Pharmacogenomicsin CNS disorders

Subbu

Apparsundaram, PhDCSO, V ClinBiosubbu@vclinbio.com+1 862 485 7489www.vclinbio.com

Sri Ramachandra University

Porur

, Chennai, India

Slide2

omics

based prediction of drug response profiling

Meyer et al.,

Annu

. Rev.

Pharmacol

.

Toxicol

53:475-502, 2013

Slide3

multiple factors influence drug response

Meyer et al.,

Annu

. Rev.

Pharmacol

.

Toxicol

53:475-502, 2013

Slide4

Lack of response

Side effects

Non-adherence

trial-and-error “roller coaster”months/years of ‘trying’too many side effectsmultiple medicationsdoctor visits etcmissed work

Patient frustrations

challenges in drug therapy

Clinicians frustrations

Slide5

Ado-

Trastuzumab

Emtansine ERBB2Afatinib EGFRAnastrozole ESR1, PGRArsenic Trioxide PML/RARABosutinib BCR/ABL1Brentuximab Vedotin TNFRSF8Busulfan Ph ChromosomeCapecitabine DPYDCetuximab EGFRCetuximab KRASCisplatin TPMTCrizotinib ALKDabrafenib (1) BRAFDabrafenib (2) G6PDDasatinib BCR/ABL1Denileukin Diftitox IL2RAErlotinib (1) EGFRErlotinib (2) EGFRErlotinib (1) EGFRErlotinib (2) EGFREverolimus (1) ERBB2Everolimus (2) ESR1Exemestane ESR1

Fluorouracil (2) DPYDFulvestrant ESR1Ibritumomab Tiuxetan MS4A1Imatinib (1) KITImatinib (2) BCR/ABL1Imatinib (3) PDGFRBImatinib (4) FIP1L1/PDGFRAIrinotecan UGT1A1Lapatinib ERBB2Letrozole ESR1, PGRMercaptopurine TPMTNilotinib (1) BCR/ABL1Nilotinib (2) UGT1A1Obinutuzumab MS4A1Ofatumumab MS4A1Omacetaxine BCR/ABL1Panitumumab (1) EGFRPanitumumab (2) KRASPazopanib UGT1A1Pertuzumab ERBB2Ponatinib BCR –ABL T315I

Rituximab MS4A1Tamoxifen (1) ESR1, PGRTamoxifen (2) F5Tamoxifen (3) F2Thioguanine TPMTTicagrelor CYP2C19Tositumomab MS4A1Trametinib BRAFTrastuzumab ERBB2Tretinoin PML/RARA

FDA-pharmacogenomic biomarkers in labeling

Oncology drugs

Slide6

Drug

Therapeutic

Area HUGO SymbolAbacavir Infectious Diseases HLA-BAtorvastatin Endocrinology LDLRAzathioprine Rheumatology TPMTBoceprevir Infectious Diseases IFNL3Carglumic Acid Metabolic Disorders NAGSCarisoprodol Rheumatology CYP2C19Carvedilol Cardiology CYP2D6Celecoxib Rheumatology CYP2C9Cevimeline Dental CYP2D6Chloroquine Infectious Diseases G6PDChlorpropamide Endocrinology G6PDClopidogrel Cardiology CYP2C19Dapsone Dermatology G6PDDapsone Infectious Diseases G6PDDexlansoprazole Gastroenterology CYP2C19Dexlansoprazole Gastroenterology CYP1A2Eltrombopag Hematology F5Eltrombopag Hematology SERPINC1Esomeprazole Gastroenterology CYP2C19Fluorouracil Dermatology DPYDFlurbiprofen Rheumatology CYP2C9Glimepiride Endocrinology G6PDGlipizide Endocrinology G6PDGlyburide Endocrinology G6PD

Ivacaftor Pulmonary CFTRLansoprazole Gastroenterology CYP2C19Lenalidomide Hematology del ( 5q)Lomitapide Endocrinology LDLRMafenide Infectious Diseases G6PDMaraviroc Infectious Diseases CCR5Methylene Blue Hematology G6PDMetoclopramide Gastroentrology CYB5R1-4Metoprolol Cardiology CYP2D6Mipomersen Endocrinology LDLRMycophenolic Acid Transplantation HPRT1Nalidixic Acid Infectious Diseases G6PDNitrofurantoin Infectious Diseases G6PDOmeprazole Gastroenterology CYP2C19Pantoprazole Gastroenterology CYP2C19Peginterferon alfa-2b Infectious Diseases IFNL3Pegloticase Rheumatology G6PDPerphenazine Psychiatry CYP2D6Phenytoin Neurology HLA-BPrasugrel Cardiology CYP2C19Pravastatin Endocrinology LDLRPrimaquine Infectious Diseases G6PDPropafenone Cardiology CYP2D6Propranolol Cardiology CYP2D6Quinidine Cardiology CYP2D6

FDA-pharmacogenomic biomarkers in labeling

other drugs

Slide7

Drug

Therapeutic

Area HUGO Symbol

Quinidine Cardiology CYP2D6Quinine Sulfate Infectious Diseases G6PDRabeprazole Gastroenterology CYP2C19Rifampin, Infectious Diseases NAT1-2Rosuvastatin Endocrinology LDLRSimeprevir Infectious Diseases IFNL3Sodium Nitrite Antidotal Therapy G6PDSofosbuvir Infectious Diseases IFNL3Succimer Hematology G6PDSulfamethoxazole and Trimethoprim Infectious Diseases G6PDTelaprevir Infectious Diseases IFNL3Terbinafine Infectious Diseases CYP2D6Ticagrelor Cardiology CYP2C19Tolterodine Genitourinary CYP2D6Voriconazole Infectious Diseases CYP2C19Warfarin (1) Cardiology or Hematology CYP2C9Warfarin (2) Cardiology or Hematology VKORC1Warfarin (3) Cardiology or Hematology PROC

FDA-pharmacogenomic biomarkers in labeling

other drugs

PharmGKB

:

http

://www.pharmgkb.org

Slide8

Amitriptyline

Aripiprazole

AtomoxetineCitalopramClomipramineClozapineCodeineDesipramineDextromethorphan & QuinidineDiazepamDoxepinFluoxetine

FluvoxamineIloperidoneImipramineModafinilNortriptylineParoxetinePerphenazinePimozideProtriptylineRisperidoneTetrabenazineThioridazine

CYP2D6

Phenytoin

CYP2C19

Citalopram Clobazam DrospirenoneEthinyl Estradiol

HLA-B

FDA – CNS Drugs: pharmacogenomic biomarkers in labeling

HLA-A HLA-B

Carbamazepine

Slide9

# of SNPs per CYP

# drugs metabolized per CYP

cytochrome P450 enzymes (CYPs)

Preissner

et al. 2013

PLOS one : e 8562

CYP2D6

CYP2C19

Slide10

Tricyclic antidepressant metabolism by

CYP2D6

and CYP2C19

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Parent drug

CYP2C19

metabolite

CYP2D6

metabolite

Therapeutic drug

monitoring

Amitriptyline

Nortriptyline

hydroxy

-amitriptyline

amitriptyline + nortriptyline

Clomipramine

desmethyl

-clomipramine

hydroxy-clomipramine

clomipramine + desmethyl-clomipramine

Desipramine

--------

hydroxy-desipramine

desipramine

Doxepin

desmethyl

-doxepin

hydroxy

-doxepin

doxepin + desmethyl-doxepin

Imipramine

Desipramine

hydroxy

-imipramine

imipramine + desmethyl-imipramine

Nortriptyline

--------

hydroxy-nortriptyline

nortriptyline

Trimipramine

desmethyl-trimipramine

hydroxy-trimipramine

trimipramine

+

desmethyl-trimipramine

Slide11

Functional

StatusActivity ValueAllelesFunctional / normal activity / wild-type1*1, *2, *27, *33, *35, *45, *46, *39, *48, *53Reduced function / decreased activity0.5*9, *10, *17, *29, *41, *49, *50, *54, *55, *59, *69, *72Non-functional / no activity0*3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *31, *36, *38, *40, *42, *44, *47, *51, *56, *57, *62

association between allelic variants & enzyme activity CYP2D6

Functional Status

AllelesFunctional / normal activity / wild-type*1Loss-of-function / no or decreased activity*2, *3, *4, *5, *6, *7, *8Gain-of-function / increased activity*17

CYP2C19

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Slide12

Allele 1

Allele 2CYP2D6 DiplotypeCYP2D6 Activity ScorePhenotype*1*1xN*1/*1xN≥3.0UM*2x2*41*2x2/*412.5UM*1*2*1/*22.0EM*1*17*1/*171.5EM*2*3*2/*31.0EM*1*4x2*1/*4x21.0EM*10*10*10/*101.0EM*4*10*4/*100.5IM*5*6*5/*60PM

CYP2D6 genotypes with resulting activity scores and phenotype classification

EM = extensive metabolizer; PM = poor metabolizerIM = intermediate metabolizer; UM = ultrarapid metabolizer

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Slide13

Predicted Metabolizer Phenotype (Range Multi-Ethnic

Frequency

a)Allele*1*2*1xN or *2xN*3*4 or *4xN*5*6*9*10*17*41*1EM EM UMEMEM EM EM EMEM EM EM *2 EM UMEM EM EM EM EMEMEMEM *1xN or *2xN  UMEM or UMEM or UMEM or UMEM or UMUMUMUMUM*3   PM PM PM PM IMIMIMIM*4    PM PM PM IMIM IM IM *5     PMPM IMIM IM IM *6      PM IMIM IM IM*9       EMEMEMEM*10        EMEMEM*17         EMEM*41          EM

predicted metabolizer phenotypes based on CYP2D6 diplotypes

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Slide14

Predicted Metabolizer Phenotype (Range Multi-Ethnic

Frequency

a)Allele*1*2*3*4*5*6*7*8*17*1EMIMIMIMIMIMIMIMUM*2 PMPMPMPMPMPMPMIM*3  PMPMPMPMPMPMIM*4   PMPMPMPMPMIM*5    PMPMPMPMIM*6     PMPMPMIM*7      PMPMIM*8       PMIM*17        UM

predicted metabolizer phenotypes based on CYP2C19 diplotypes

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Slide15

C

African

AmericanEast AsianEuropeanMiddle EasternOceanianSouth/Central Asian*1c0.680.690.600.630.870.240.62*20.150.120.290.150.120.610.35*30.00520.000280.0890.00420.0110.150.024*40.000930.00240.000490.0025NDND0.00*5ND0.000.000620.000073NDND0.00*60.000.000.000.00017NDND0.00*80.000.00120.000.0035NDNDND*170.160.180.0270.21NDNDND

frequencies of CYP2C19 alleles in major race/ethnic groups

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Slide16

5-HT

SLC6A4

HTR1AHTR1BHTR2AHTR3AHTR3BHTR6TPH1TPH2

NorepinephrineCOMTMAO-ASLCA2

dopamineSL6A3DRD4

HPA axisFKBP5NR3C1

Signal transduction & growth factorsBDNFGNB3OPRM1

enzymesACEGSK3BIDO2

glutamatergicGR1K4

other pathways modulating antidepressant

action

Slide17

antidepressant treatment algorithms

Assurex

GeneSight

Slide18

clinical implications

Patient stratification

procedures in clinical practice will be useful to achieve greater efficacy and safety

Genotyping (stratification)

prior to treatment may provide tailored therapies

Regional differences in

genotypes (stratification)

should be

investigated to facilitate dosing and regimen

Slide19

Omic

technologies can be applied in different phases of drug discovery and development

Sri Ramachandra University

Chennai, India

Patient stratification

Efficacy & Safety readouts

Slide20

Slide21

Slide22

Allele

African

African AmericanCaucasian (European + North American)Middle EasternEast AsianSouth/Central AsianAmericasOceanian*1c0.390.410.520.590.340.530.620.70*2d0.200.120.270.240.120.310.240.012*30.00030.00340.0130.00130.000.000.00520.00*40.0330.060.180.0760.00450.0650.110.011*50.060.0580.0280.0230.0580.0250.0160.049*60.000.00270.00910.00960.00020.000.0050.00*70.000.000.00120.000.00ND0.000.00*80.000.000.00030.000.00ND0.00150.00*90.00100.00540.020.000.00080.0140.0130.00*10e0.0670.0430.0280.0350.420.190.0340.016*140.00130.000.000.000.00920.000.00470.00*17f0.190.180.00270.0140.00020.00380.0230.0005*360.000.00560.000.000.017NDND0.00*41g0.100.100.0920.220.0220.100.0570.00xNh0.0750.0430.0280.0670.0150.0130.0330.088*1xNi0.0140.00440.00770.0380.00310.00500.00780.11*2xNi0.0150.0160.0130.0360.00420.00500.0230.00*4xNi0.0140.0200.00280.000.000.000.00360.00

frequencies of CYP2D6 alleles in major race/ethnic groups

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Slide23

o

mics

based prediction of drug response profiling

Slide24

Slide25

Slide26

Slide27

Lack of response:

~ 50% of patients with depression do not respond to their first treatment

Side effects: In the clinical studies, up to 30% of patients discontinues treatment due to intolerable side effectsNonadherance: Up to 7% of patients receiving prescription for antidepressant drugs are non-adherent, with side effects most common reason

trial-and-error “roller coaster”months/years of ‘trying’too many side effectsmultiple medicationsdoctor visits etcone size fits all

Patient frustrations

challenges in antidepressant therapy

Slide28

Slide29

Slide30

Supplemental Table S4.

Association between allelic variantsa and CYP2D6 enzyme activity

Functional StatusAllelesReferencesFunctional / normal activity / wild-typea*157Loss-of-function / no or decreased activity*2, *3, *4, *5, *6, *7, *858-64Gain-of-function / increased activity*1765-67

Slide31

Tricyclic antidepressant metabolism by

CYP2D6

and CYP2C19

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Slide32

Tricyclic antidepressant metabolism by

CYP2D6

and CYP2C19

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Slide33

GWAS studies

Slide34

pharmacogenomics: phenytoin

Clinical Pharmacology & Therapeutics 93: 402-408, 2013

Slide35

Slide36

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