Pharmacogenetics and the Promise of Individualized Medical Care John Deeken, M.D. May 18, 2009.

Pharmacogenetics and the Pharmacogenetics and the Promise of Individualized Promise of Individualized

Medical CareMedical Care

John Deeken, M.D.John Deeken, M.D.

May 18, 2009May 18, 2009

PharmacogenomicsPharmacogenomics

Non-Responders and Patients Experiencing

Severe Toxicity

All patients with same diagnosis

Responders and Patients not Experiencing

Severe Toxicity

Sources of Pharmacokinetic and Sources of Pharmacokinetic and Pharmacodynamic VariabilityPharmacodynamic Variability

Drug Specific:Dose & Schedule

Dosage formMorphometric:Body SizeBody Composition

Genetics:

Environment:Drug-drug interactions

Drug-CAM interactionsDrug-formulation interactions

Drug-food constituent interactions

Physiologic:DiseaseHepatic FunctionRenal Function

Demographic:AgeRace/EthnicitySex

VariabilityVariability

PharmacogeneticsPharmacogenetics

Implications of polymorphismson Pharmacokinetics

Implications of polymorphismson Drug Effect

• Drug Absorption• Drug Distribution • Drug Elimination• Drug Metabolism• Drug Activation

• Receptors• Target Proteins

Genetic PolymorphismsGenetic Polymorphisms

Single Nucleotide Polymorphisms Single Nucleotide Polymorphisms (SNPs)(SNPs)Non-synonymous and Non-synonymous and

synonymoussynonymous Upstream/downstream regulatory Upstream/downstream regulatory

regionsregions Copy numberCopy number

Transporters Mediate Transporters Mediate AbsorptionAbsorption

www.solvo.com

Transporters Mediate Bile Transporters Mediate Bile EliminationElimination

www.solvo.com

Transporters Mediate Renal Transporters Mediate Renal EliminationElimination

www.solvo.com

ABCG2 (BCRP, ATP-binding cassette)ABCG2 (BCRP, ATP-binding cassette)

Involved in intrinsic or acquired multidrug Involved in intrinsic or acquired multidrug resistance (MDR) phenotype of tumor cellsresistance (MDR) phenotype of tumor cells

ABCG2 ABCG2 encodes a half transporterencodes a half transporter

Located on chromosome 4q-22Located on chromosome 4q-22

66 kb; 16 exons; 15 introns 66 kb; 16 exons; 15 introns

69 Known genetic polymorphisms including 65 69 Known genetic polymorphisms including 65 SNPs; 13 SNPs in exons; 7 SNPs cause amino acid SNPs; 13 SNPs in exons; 7 SNPs cause amino acid substitutionssubstitutions

Location of ABCG2 C421A and its functional Location of ABCG2 C421A and its functional consequencesconsequences

OUT

MEMBRANE

IN

200100

300

400

500

600

ATP SITE

N Terminus

C Terminus

MXR SNPs V12M

Q141K E366E L475L D620N

E366E

V12M

L475L

Q141K

D620N

R482

Non-synonymous ABCG2 Q141K SNP: substituted amino acid residue

- The 421C to A transition at exon 5 leads to a Lys to Gln amino acid substitution at codon 141 (Q141K)

- Functional studies suggest that the C421A polymorphism has:

1. Reduced topotecan transport

2. Reduced protein expression in vitro

3. A 3-fold higher diflomotecan AUC after i.v. administration

ABCG2 pharmacogenetics: influence on imatinib ABCG2 pharmacogenetics: influence on imatinib (STI-571; Gleevec) pharmacokinetics(STI-571; Gleevec) pharmacokinetics

Parameter WT* Het** P

Cmax 11.2 36.5 0.0064

AUC 140 536 0.0063

* N = 32

** N = 4

Patients with GIST treated with imatinib at dose ranging, 100 – 1000 mg p.o.

Lepper E, et al (Figg), Pro ASCO 2005

Drug Metabolizing Enzymes

Evans and Relling, Science 286: 487-91, 1999

PGx of Drugs Used in Medical OncologyPGx of Drugs Used in Medical Oncology

Drug Pathway Variability in CL

Amonafide N-acetyl transferase (NAT) >3-fold

Busulfan Glutathione S-transferase (GST) 10-fold

Docetaxel Cytochrome P-450 (CYP) 3A4/3A5 4 to 9-fold

5-Fluorouracil Dihydropyrimidine dehydrogenase 10-fold

6-Mercaptopurine Thiopurine methyltransferase >30-fold

Evans and Relling, Science 286: 487-91, 1999

Example of anticancer drug metabolism by polymorphic enzymes

Warfarin (Coumadin)Warfarin (Coumadin)

Name Your PoisonName Your Poison

Warfarin (Coumadin)Warfarin (Coumadin) Used for chronic Used for chronic

anticoagulationanticoagulation INR and lab testingINR and lab testing Two enantiomers (R- and Two enantiomers (R- and

S-)S-)

WarfarinWarfarin

Name Your PoisonName Your Poison Used for chronic anticoagulationUsed for chronic anticoagulation INR and lab testingINR and lab testing Two enantiomers, R and STwo enantiomers, R and S

Warfarin Metaboli

sm

Importance of CYP2C9

Warfarin Pharmacodyna

mics

Importance of

VORC1

Warfarin -PGxWarfarin -PGx

PGx: CYP2C9 and VORC1PGx: CYP2C9 and VORC1 Expert Committee Recommendation to Expert Committee Recommendation to

FDAFDA Consider PGx testing, but needs further Consider PGx testing, but needs further

studystudy Multiple studies currently ongoing, main Multiple studies currently ongoing, main

U.S. study funded by NIHU.S. study funded by NIH Medicare announced May 4 that it will not Medicare announced May 4 that it will not

pay for genetic testing at this timepay for genetic testing at this time Will pay for genetic testing in clinical trialsWill pay for genetic testing in clinical trials

PGx and Clopidogrel PGx and Clopidogrel (Plavix)(Plavix)

Thienopyridine inhibitor of platelet P2YThienopyridine inhibitor of platelet P2Y1212 ADPADP

Prodrug, requires activitation by CYP450 Prodrug, requires activitation by CYP450 enzyme(s) and also inactivated by CYP450 enzyme(s) and also inactivated by CYP450 enzyme(s) and other esterasesenzyme(s) and other esterases

Much variability between patients in Much variability between patients in terms of pK and PD (platelet aggregation)terms of pK and PD (platelet aggregation)

PGx and Clopidogrel PGx and Clopidogrel (Plavix)(Plavix)

Mega et al (NEJM Jan 22, 2009): Mega et al (NEJM Jan 22, 2009): healthy volunteers pK (n=162)healthy volunteers pK (n=162) Cardiac patients on TRITON-TIMI study (n=1477)Cardiac patients on TRITON-TIMI study (n=1477)

Pts with at least one reduced function variant Pts with at least one reduced function variant in in CYP2C19CYP2C19:: 32% reduction in active drug plasma levels32% reduction in active drug plasma levels 53% increase risk of death from CV causes, MI, or 53% increase risk of death from CV causes, MI, or

stroke (12.1% vs 8.0%, HR 1.53)stroke (12.1% vs 8.0%, HR 1.53) Three-fold increased risk of stent thrombosis Three-fold increased risk of stent thrombosis

(2.6% v. 0.8%)(2.6% v. 0.8%) Caveat: research paid for by Eli Lilly and Daiichi Caveat: research paid for by Eli Lilly and Daiichi

Sankyo since study was of prasugrel vs clopidogrelSankyo since study was of prasugrel vs clopidogrel FDA currently evaluating evidence to FDA currently evaluating evidence to

consider requiring PGx testing before consider requiring PGx testing before starting clopidogrelstarting clopidogrel

Irinotecan (CPT-11)Irinotecan (CPT-11)

Topoisomerase I inhibitorTopoisomerase I inhibitor Metabolized to active compound SN-38Metabolized to active compound SN-38 Used in colon cancerUsed in colon cancer DLT – diarrheaDLT – diarrhea SN-38 inactivated by UGT1A1 SN-38 inactivated by UGT1A1

glucoronidationglucoronidation Polymorphism in UGT1A1 (Polymorphism in UGT1A1 (UGT1A1*28UGT1A1*28) )

leads to diminished inactivation, higher leads to diminished inactivation, higher drug levels, and higher toxicitydrug levels, and higher toxicity

Mathijessen RHJ et al. Clin Cancer Res 2001:2168

Pharmacogenomics and Oncology:Pharmacogenomics and Oncology:

New label for Irinotecan, July 2005:New label for Irinotecan, July 2005:

FDA approved test in December, 2005FDA approved test in December, 2005

We still do not know what to do with doseWe still do not know what to do with dose

TamoxifenTamoxifen

SERMSERM Used for adjuvant therapy in ER/PR+ Used for adjuvant therapy in ER/PR+

breast CAbreast CA Metabolite Endoxifen is 100x more Metabolite Endoxifen is 100x more

effective than parent compoundeffective than parent compound CYP2D6 mediates activation of CYP2D6 mediates activation of

Tamoxifen to EndoxifenTamoxifen to Endoxifen

TamoxifenTamoxifen

Importance Importance of CYP2D6of CYP2D6




• Drug Absorption• Drug Metabolism• Drug Elimination• Drug Distribution• Drug Activation


Beta Receptor and Beta Receptor and HTN/CHFHTN/CHF

Beta blockers – well namedBeta blockers – well named ADRB1 and ADRB2ADRB1 and ADRB2 In ADRB1, 2 common functional

polymorphisms (Ser49Gly and Gly389Arg). In HTN, pts treated with Metoprolol, Gly389:

WT/WT: 10.4% drop in SBP WT/Variant: 2.8% Variant/Variant: 1.1% Similar differences found in HR and SBP at rest and with

exercise

In CHF, WT patients need more medications/dosages

Liu J et al. Clin Pharmacol Ther 2003, 2006

Terra SJ, et al. Clin Pharmacol Ther 2006

Beta Receptor and ACSBeta Receptor and ACS




• Drug Absorption• Drug Metabolism• Drug Elimination• Drug Distribution• Drug Activation


Pharmacogenomics and Pharmacogenomics and FDAFDA

““Pharmacogenomics holds great promise to Pharmacogenomics holds great promise to shed scientific light on the often risky and shed scientific light on the often risky and costly process of drug development, and to costly process of drug development, and to provide greater confidence about the risks provide greater confidence about the risks and benefits of drugs in specific and benefits of drugs in specific populations. Pharmacogenomics is a new populations. Pharmacogenomics is a new field, but we intend to do all we can to use it field, but we intend to do all we can to use it to promote the development of medicines.”to promote the development of medicines.”

--Mark McClennan, M.D.Mark McClennan, M.D. FDA Commissioner Nov, FDA Commissioner Nov,

20032003

Pharmacogenomics and Pharmacogenomics and FDAFDA

2002: ‘Safe Harbor’ concept for data submissions2002: ‘Safe Harbor’ concept for data submissions 2003: Draft guidance for industry to submit genomic 2003: Draft guidance for industry to submit genomic

data data 2004: 2004:

PG identified as ‘Key opportunity’ in FDA’s PG identified as ‘Key opportunity’ in FDA’s ‘Critical Path’ for the future‘Critical Path’ for the future

Interdisciplinary PG Review Group Formed. Interdisciplinary PG Review Group Formed. First Voluntary Genomic Drug Submission (VGDS) First Voluntary Genomic Drug Submission (VGDS)

received by FDAreceived by FDA 2005 2005

Genomics Website: www.fda.gov/cder/genomicsGenomics Website: www.fda.gov/cder/genomics Final rules published on guidance for industryFinal rules published on guidance for industry

Biomarker/Genetic targets:Biomarker/Genetic targets:AbbottAbbottJohnson & JohnsonJohnson & JohnsonRoche (Swiss)Roche (Swiss)

Pharmacogenomics for individualized Rx:Pharmacogenomics for individualized Rx:PfizerPfizerBristol-Myers-SquibbBristol-Myers-SquibbGenentechGenentech

Molecular diagnostic kits/devices:Molecular diagnostic kits/devices:Roche expected sales this year: $6.5 billionRoche expected sales this year: $6.5 billion

eexpected sales by 2010: $12 billionxpected sales by 2010: $12 billion

Pharmacogenomics - IndustryPharmacogenomics - Industry

Pharmacogenomics:Pharmacogenomics:IndustryIndustry

First clinically available, FDA-approved genotype test inFirst clinically available, FDA-approved genotype test in2005 (Roche - Amplichip)2005 (Roche - Amplichip)

Chip for SNPs in all CYP450 genes, 2005 (GE)Chip for SNPs in all CYP450 genes, 2005 (GE)

Chip for p53 mutations expected mid-2006 (Roche)Chip for p53 mutations expected mid-2006 (Roche)

Affymetrix/ParAllele DMET Chip - 1,300 SNPs covering 185 Affymetrix/ParAllele DMET Chip - 1,300 SNPs covering 185 genes (enzymes and transporters) involved in druggenes (enzymes and transporters) involved in drug

metabolism Spring, 2006metabolism Spring, 2006

Pharmacogenomics and Pharmacogenomics and NIHNIH

Pharmacogenomics Research Network (PGRN)Pharmacogenomics Research Network (PGRN) Initiated based on NIH Scientific Advisory Panel Initiated based on NIH Scientific Advisory Panel

recommendation in 1999recommendation in 1999 Launched in year 2000Launched in year 2000 $140 million for first 5 years (UO1 mechanism)$140 million for first 5 years (UO1 mechanism) 12 centers funded from 2000 to 200512 centers funded from 2000 to 2005 Second 5-year period from 2005-2010, $150 Second 5-year period from 2005-2010, $150

million, again with 12 centers funded (not same as million, again with 12 centers funded (not same as original)original)

NIGMS (General Medical Science) is lead NIH NIGMS (General Medical Science) is lead NIH institute, with other institutes participating, institute, with other institutes participating, including NHLBI, NIDA, NCI, NIEHS, NHGRI, including NHLBI, NIDA, NCI, NIEHS, NHGRI, NIMH, NLM, and ORWHNIMH, NLM, and ORWH

Non-Responders and Patients Experiencing

Severe Toxicity

All patients with same diagnosis

Responders and Patients not Experiencing

Severe Toxicity

PGx – The Future of Individualized Medicine?

Pharmacogenetics and the Promise of Individualized Medical Care John Deeken, M.D. May 18, 2009.

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Transcript of Pharmacogenetics and the Promise of Individualized Medical Care John Deeken, M.D. May 18, 2009.