The Right Drug in the Right Dose for the Right Patient-Personalized Medicine Comes True Hong-Hao Zhou Institute of Clinical Pharmacology Pharmacogenetics

The Right Drug in the Right Dose

for the Right Patient-Personalized Medicine Comes

True

Hong-Hao Zhou

Institute of Clinical PharmacologyPharmacogenetics Research Institute

Central South UniversityChangsha, Hunan, China

International Conference on Pharmacovigilence and Drug SafetyNov 30, 2010. Changsha

PGt and PGx

Pharmacogenomics (PGx) :

−The study of variations of DNA and RNA characteristics as related to drug response.

Pharmacogenetics (PGt) :

−The study of variations in DNA sequence as related to drug response. A subset of pharmacogenomics (PGx).

= Pharmacology + Genetics. Purpose: Genetic predisposition to drug effect Individualized pharmacotherapy The right drug at right dose for the right people Revolutionize medicine

Variability within populations (intra-ethnic variations) greater than differences between populations (Inter-ethnic differences)

Nu

mb

er

of

Su

bje

cts

Plasma Concentration

Population AIncreased Risk

Therapeutic Failure

Population BIncreased Risk

Toxicity

Therapeutic Window

Inter-ethnic differences

Intra-ethnic differences

Inter-ethnic/individual Variations

Ageelderlychildrenneonates

Sex

Height/Body Weight

ConcomitantDisease

Disease Process

Factors Determining Interindividual variations in Drug Response

Organ FunctionLiver, Kidney, Cardiac

Environmental Factors

diet / smoking / comedications

Interindividual Variability in

Drug Response

Genetic polymorphisms

Heritability of Drug Metabolism

Genes Environment

•0% •10% •20% •30% •40% •50%•60% •70% •80% •90%•100%

Diabetes mellitus LO

Breast cancer

MI (males)

Essential hypertension

Coronary artery disease

Diabetes mellitus EO

Diphenylhydantoin

Lithium

Sodium salicylate

Amobarbital

Dicumarol

Aspirin

Antipyrine

Phenylbutazone

Single nucleotide polymorphisms

C A G C C C A A C T5’ 3’

CYP2C9 gene

430C

CYP2C9*1CYP2C9*2

T

Normal enzyme

No enzymatic activity

9 Exon 55kb 490 AA

10

q24.2

Ch

rom

osom

e 1

0

A Key to Human Individuality

A key to interindividual variations in drug metabolism and response

T (Arg144Cyp)

1975 ： Debrisoquin polymorphism

1985 ： PCR application

1990 ： CYP2D6 alleles

X

XX

Nortriptylline 500mg 100-450mg 10-20mg （ normal dose ）

Debrisoquin/4-OH-debrisoquin

Su

bje

ct

nu

mb

er

CYP2D6 genotype/phenotype

Pharmacogenetic Principles

Pharmacodynamics Pharmacokinetics

Variability in drugefficacy and toxicity

Genome

Gene variations (genetic polymorphism)

Drug metabolizing enzymes

Drug transportersDrug targets

Gene Name Allele Associated phenotype

CYP2C19 Cytochrome p450 2C19

*2 ,*3 Extensive metabolizers have decreased response to omeprazole for Helicobacter pylori infection

CYP2C9 Cytochrome p450 2C9

*2 ,*3 Non-wt alleles associated with reduced warfarin daily dose requirement

CYP2D6 Cytochrome p450 2D6

Many inactive alleles, such as *3, *4 and *5

Non-wt alleles associated with susceptibility to tardive dyskinesia in response to antipsychotics

NAT2 N-acetyltransferase2

Slow acetylator alleles include NAT2 *5B,NAT2 *6A,NAT2 *7A or B, NAT2 *14A or B

Slow-acetylator status of NAT2 increased risk of antituberculosis drug-induced hepatotoxicity

TPMT Thiopurine methytransferase

TPMT *2,TPMT *3A,TPMT *3C

Homozygotes for non-wt alleles at high risk of severe haematopoietic toxicity after thiopurine treatment ;heterozygotes intermediate risk of dose-limiting toxicity

Genetic variants of DME found to be significantly associated with drug response in at least two

studies

Goldstein DB, et al. Nature Reviews 2003;4: 937-947

Nature Reviews 2003;4:937-947


GSTM1 Glutathione S-transferase M1

GSTM1-null Null carriers have increased survival time and a progression-free interval following paclitaxel and cisplatinum treatment for ovarian cancer, decreased risk of relapse for cytotoxic therapy for leukaemia

GSTM3 Glutathione S-transferase M3(brain)

GSTM3 *A/ GSTM3 *B

GSTM1 *0/GSTM3 *A haplotype less likely to show a beneficial response to D-penicillaminein rheumatoid arthritis, *3A has increased risk of cisplatin ototoxicity

GSTP1 Glutathione S-transferase-π

lle105Val Val associated with increased survival for 5-fluorouracil and oxaloplatin therapy for colorectal cancer, and following therapy for multiple myeloma

GSTT1 Glutathione S-transferase-η1

GSTT1-null(homozygote frequent ;deletion)

GSTT1 associated with susceptibility to tacrine hepatotoxicity and troglitazone hepatotoxicity in combination with GSTM1-null allele


studies

Goldstein DB, et al. Nature Reviews 2003;4: 937-947

Nature Reviews 2003;4:937-947


DPYD Dihydropyrimidine dehydrogenase (DPD)

DPYD *2A(IVS14+1G>A)

*2A associated with severe toxicity and fatal outcomes for 5-fluorouracil treatment

UGT1A1 UDP-glucurono-syltransferase 1A1

UGT1A1 *28 *28 associated with increased chance of developing diarrhoea and leukopaenia during irinotecan therapy

COMT Catechol O-methyltransferase

Val108/135Met Met associated with higher daily neuroleptic dosage and poor response

BCHE ButyryIcholinesterase Several mutations including Asp70Gly (dibucaine or atypical variant) and Ala539Thr (K allele)

Variants associated with adverse effects in response to succinylcholine


studies

Genotype, Risk and Events

0.1

1

10

100

1000

10000

100000

1E-10 1E-09 1E-08 1E-07 0.000001 0.00001 0.0001 0.001 0.01 0.1 1

Ind

ivid

ual

ris

k

5000 events

Genotype frequency

Ind

ivid

ual ri

sk

Carbamazepine Induced SJS

Carbamazepine

Epileptic seizures , neuralgia, and other neural diseases

ADR: SJS/TEN

HLA-B*1502

High fever, malaise, blistering, lesions. skin

detachments, mortality 30~40%

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

Country/Region

HLA-B*1502 in normal population (%)

HLA-B*1502 in CBZ-SJS/TEN

(%)

USA 0% Caucasian 4.9% Asian

Europe Rare 1-2; Ireland 0

Taiwan 8.6% Han; 5.7-8.6Thai Han 100

Hong Kong

14.5 Han 100

Singapore 5.7% Chinese; 12% Malay; 8.3% Indian

Malaysia 15.7% Malay; 5.7% Chinese; 0% Indian; 1% Maynmese

Malay 75 Indian 100

Thailand 8.5-27.5% 83.3

Indonesia 16%

India 1.9% Mumbai; 6%Kandesh; 4% Bhil; 1%Punjab

Japan 0.2%

Korea 0.4%

Neurology Asian, 2008; 13, 15-21

HLA-B*1502 And Carmazepine Induced SJS/TEN In Asian

Prospective evaluation of genotype directed Metoprolol monotherapy in hypertension

Metoprolol:

DME: CYP2D6; CYP2D6*10-low activity

Target: 1-receptor; Gly389Gly-low sensitivity

Low activity DME + High sensitivity target 12.5mg

Low activity DME + High/medium sensitivity targetMedium activity DME +medium sensitivity targetLow activity DME + Low sensitivity target

High activity DME + Low sensitivity target 50mg

25mg

HP Pts

n=422

CYP2D6*1*10+Arg389ArgCYP2D6*10*10+Arg389Arg/Gly389ArgCYP2D6*1*10+Arg389ArgCYP2D6*10*10+Arg389Arg/Gly389Arg

CYP2D6*1*1+Arg389Arg/Gly389ArgCYP2D6*1*10+Gly389Arg CYP2D6*10*10+Gly389Gly


CYP2D6*1*1/CYP2D6*1*10+Gly389GlyCYP2D6*1*1/CYP2D6*1*10+Gly389Gly

Ran

dom

ized

Ran

dom

ized

CYP2D6*1*10+Arg389ArgCYP2D6*10*10+Arg389Arg/Gly389ArgCYP2D6*1*10+Arg389ArgCYP2D6*10*10+Arg389Arg/Gly389Arg



CYP2D6*1*1/CYP2D6*1*10+Gly389GlyCYP2D6*1*1/CYP2D6*1*10+Gly389Gly

25mg, bid 12w

125mg, bid 12w

25mg, bid 12w

50mg, bid 12w

N=14

100

104

N=14

91

104


Con

ven

tion

al

Con

ven

tion

al

Pers

on

alize

dP

ers

on

alize

d

A, Non-genotype directed therapy

B, Genotype directed therapy

0

2

4

6

8

10

12

14

16

18

20

⊿ SBP ⊿ DBP

Blo

od

pre

ssu

re d

ecre

ase (

mm

H

g)

P= 0.118

P = 0.009

A1+A3

B1+B3

0

2

4

6

8

10

12

14

16

18

⊿SBP ⊿DBPB

lood

pre

ssu

re d

ecre

ase (

mm

H

g)

P = 0.027

P = 0.001

Liu J and Zhou HH,2008


Personalized Medicine

PatientPatient Drug ADrug A ADRADR

Drug BDrug B

Evidence Based Medicine

PatientPatient DiagnosticDiagnosticTestTest

ADRADR

TargetedTargetedDrugDrug

Personalised Medicine

Health System

Evidence Based

Medicine

Personalized Medicine

Efficacy vary-wasted resources and timeAdverse effects are common and unpredictable

Direct treatment in an individualized mannerDetermine who to treat at all

Benefits from personalized medicine

Patients Reduced uncertainty, improved care and less

exposure to ineffective treatments Physicians

Better options and outcomes for patients Regulators

Increased safety and efficacy Payers

More efficient use of our healthcare dollar Policy-makers

More cost-effective healthcare Industry

Innovative products that offer a clear improvement for patients

Because we know more specific information, we can…

Diagnose more precisely Provide more effective treatment.

Select specific treatment that best fits disease

Target the medication to the disorder.

Avoid adverse drug reactions. Avoid delay from false starts.

Predict risk before symptoms occur

Provide earlier treatment. Take preventive action.

Manage disease more effectively

Eliminate unnecessary treatment.

Provide better timing. Adjust treatment as disease

changes.

Service for Tailored Therapy in CSU

To translate PGx/PGt knowledge to the treatment of patients, a Tailored Therapy Center was founded in October, 2004 at Central South University

The Center is pioneering the translating PGx/PGt to personalized medicine and use state-of-the-art research facilities to perform advanced testing of a patient's genotype to determine which medications are effective against it, and what dosage levels are needed to treat it, then devise a treatment regimen that is unique to each individual patient.

The goal of this tailored approach

Don’t treat non-responders (patient stratification)

Don’t treat those most likely to be affected by toxicity (patient stratification)

Adjust dose to maximize efficacy while avoiding toxicity for each individual patient (individualized therapy)

- To deliver the most effective therapy, while minimizing possible side effects related to drug dosing.

Personalized Medicine in CSU

Oct. 2004: Consultant Center

Feb, 2006: Genetic Test Center

Sep. 2010 ， Xiang Ya Medical

Laboratory, Central South

University

Oct., 2004 Consultant Center for Tailored Therapy

Personalized Medicine in CSU

PGt and PGx Genetic Test Center

Xiangya Medical Laboratory

Feb., 2006

Sep., 2010

Clinical Service for Personalized Medicine in CSU

Xiangya Medical Lab Mutant Alleles

DME Transporters Receptors

Large dose

Modulation dose

Reduce dose or Change drug

Clinical Diagnosis

Hospital Pts

Genetic Diagnosis

Clinical Service for Personalized Medicine in CSU

Commonly prescribed

Narrow therapeutic window

Great hazard if outside of therapeutic window

Significant variability in individual response to standard dosages

No good alternative

Perfect Drug for PGx Intervention

Gene tested Allele tested Clinical relevance

K-Ras( EGRF signal protein Condons 12/13 Cetuximab, panitumumab efficacy prediction

CYP3A5 CYP3A5*3 Tacrolimus initiative dose prediction

GSTP1 (Glutathione-S-transferase) GSTP1*B(A342G) Cisplatin, Oxaliplatin toxicity & efficacy prediction

UGT1A1 (glucuronyltransferase) UGT1A1*28 Irinotecan toxicity prediction

UGT1A1*6

TYMS (thymidylate synthase) TYMS_2R/3R 5-Fluorouracil toxicity and efficacy prediction

CDA (cytidine deaminase) CDA*3 Gemcitabine myelosuppression toxicity prediction

TPMT (thiopurine methyltransferase)

TPMT*3C Mercaptopurine, azathioprine toxicity and efficacy prediction

EGFR (epidermal growth factor R) EGFR_I/D Gefitinib, erlotinib efficacy prediction

HLA (human leukocyte antigen) HLA-B* C 1502 /A Carbamazepine skin-mucosa toxicity prediction

CYP2D6 CYP2D6*10 Β1 antagonists efficacy and dose predictionβ1-R β1 (adrenoceptor) β1R_Gly389Arg

CYP2C9 VKORC1_1639G>A --AT1 antagonists efficacy and dose prediction

Warfarin initiative dose and toxicity prediction

VKORC1 CYP2C9*3

ACE (angiotensin-convertion E) ACE_I/D ACEI efficacy and dose prediction

CYP2C19 CYP2C19*2 Clopidogrel resistance prediction

CYP2C19*3

Genetic tests for personalized therapy in CSU

Gene tested Allele tested Clinical relevance

ALDH2 (acetaldehyde dehydrogenase) exon 12(G>A)Nitroglycerol efficacy prediction (CAD)

CYP1B1 CYP1B1*3Paclitaxel efficacy prediction (breast cancer)

MDR1 (multidrug resistance gene)

MDR1-G2677T/A Paclitaxel 、 Ciclosporin efficacy

prediction (ovarian cancer, liver and kidney transplantation)

MDR1-CA3435T

MDR1-T1236C

MTHFR (tetrahydrofolic acidreductase) MTHFR C677T

5-FU toxicity prediction (ovarian cancer), efficacy prediction (gastric cancer)

Methotrexate toxicity prediction

DPYD (dihydropyrimidine dehydrogenase) DPYD*2A

5-Fluorouracil toxicity prediciton (digestive tract Cancer)

Capecitabine toxicity prediction (Recurrent breast cancer)

TYMS (thymidylate synthase) TYMS_2R/3R5-FU, raltitrexed, pemetrexed, nolatrexed toxicity and efficacy prediction

XRCC1 (X-ray repair cross-complementing group 1)

XRCC1(Ar399Glplatinums ： etoposide efficacy prediction

CYP2D6 CYP2D6*10Tamoxifen efficacy prediction

SULT1A1 (Sulfotransferase 1A1) SULT1A1*2

GSTA1 (glutathione S-transferase A1) GSTA1*BCyclophosphamide efficacy prediction

SLCO1B1 (Organic anion transport protein 1B1)

Multiple Irinotecan toxicity prediction

Genetic tests for personalized therapy in CSU

Metohods to be used

Direct sequencing (“Gold standard”Beckman, Genetic Analysis SystemFor 400-600bp

PCR/RFLP Low throughput; Common used

Allele-specific PCRFor specific gene allele; Rarely used

PyrosequencingMedium throughput For 20-40bp

Hyper throughputGene chipsllumina

Male ， 56 yr ， hypertension, school teacher

Metoprolol 20mg bid; blood pressure and sympathetic nervous excitation symptoms could not be controlled

Genetic test: 1-receptor Gly389Gly

Recommendation ： increase metoprolol dose to 180%

40mg bid; blood pressure and sympathetic nervous excitation symptoms could not be controlled

Examples: Case 1

Male, 26 yr, anxiety disorders Prescription: buspirone and Buspar

Genetic test: 2C9: EM, 2C19:EM, 2D6:IM

Recommendation: using lower initial dose

Examples: Case 2

Male, 64 yr. colorectal cancer

Prescription: Cetuximab

Genetic test: K-RAS mutations in codons 12 and 13

Recommendation: priscribe alternative medicine

Examples: Case 3

Chinese Pharmacogenomics Network

Commonly prescribed

Narrow therapeutic window

Great hazard if outside of therapeutic window

Significant variability in individual response to standard dosages

No good alternative

The Perfect Drug for PGx Intervention

Ministry of Science and Technology Pharmacogenomics Innovative Technology

Service Platform

Pre-clinical Pharmacokinetics Technology Platform

Natural Medical Products Screen and Safety Evaluation Pharmacogenomics Technology Platform

Clinical Trial and Genetic Variation Related Drug Safety Evaluation Technology Platform

Personalized Therapy Genetic Diagnostic Technology Development and Clinical Application Platform

Major diseases Genome-Wide Association Studies and Pharmacogenomics Technology Platform

Pharmacogenomics Innovative Technology

Service Platform

Purpose• Promote the integration of genetic information

into public health decision making process

• Enhance the understanding of pharmacogenetics in developing world

• Provide guidelines for medication prioritization for individual countries, using pharmacogenetic information

• Help build local infrastructure for future pharmacogenetic research studies

• 104 PGENI countries, • representing 78% of world population

104 PGENI countries; 78% of world population

PGENI International Centers

Traditional Chinese Medicine (TCM)

TCM can be toxic and numerous examples of liver, kidney and other organ damage are on record

TCM are not to the same extend submitted to stringent regulation and control

TCM can be contaminated or adulterated with prescription drugs

42

Evolution of the Essential Drug List in China

3000-

2500-

2000-

1500-

1000-

500-

0-1981

edition1996

edition1998

edition2000

edition2002

edition

Western medicine TCM

280

Data from Sun X, et al; 2004

699740

770

759

18121570

2019

1242

Necessity of Necessity of safety monitor for TCM monitor for TCM

Limited knowledge about the Limited knowledge about the

ingredients ingredients

Limited knowledge about their effects Limited knowledge about their effects

Often a lack of stringent quality Often a lack of stringent quality

control control

The heterogenous nature of herbal The heterogenous nature of herbal

medicinesmedicines

Reporting of ADR’s caused byReporting of ADR’s caused by TCM TCM

ADR’s caused by TCM are unrecognized ADR’s caused by TCM are unrecognized

The safety of TCM is overestimatedThe safety of TCM is overestimated

Sometimes ADR’s are misconstrued as Sometimes ADR’s are misconstrued as part of the healing actionpart of the healing action

TCM practitioners are less likely to report TCM practitioners are less likely to report

Patients who resort to TCM are more Patients who resort to TCM are more likely to believe unscientific claims likely to believe unscientific claims

Patients who resort to TCM are less likely Patients who resort to TCM are less likely to report what they sufferedto report what they suffered

There is a need for greater awareness that a need for greater awareness that ADRs due to a conventional drug therapy in ADRs due to a conventional drug therapy in China, might be due toChina, might be due to

− TCMTCM

− TCM-western medicine interaction.TCM-western medicine interaction.

The educating of doctors, pharmacists, he educating of doctors, pharmacists, industry and patients about drug safety and industry and patients about drug safety and the importance of PGt and PGx can certainly the importance of PGt and PGx can certainly be listed among the greatest challenges.be listed among the greatest challenges.

The genetic polymorphism of DME may The genetic polymorphism of DME may influence the individual variations in ADR of influence the individual variations in ADR of TCM and TCM-drug interactions.TCM and TCM-drug interactions.

Challenge for Personalized Medicine in Avoiding of TCM induced ADRs

Conclusions Over the last 3 decades, my institute has

been vast interest in and focus on the PGt/PGx research and clinical application aimed to personalized medicine.

There is general agreement that utilizing genome technology may assess individual risk and ensure the delivery of the “right drug, right dose, for the right patients”.

However, there’s no doubt that personalized medicine is at an early stage. We should avoid overheated initial expectations.

We need more clinical trials at multiple centers in large numbers of patients.

http:/www.csupharmacol.com

Documents

The Right Drug in the Right Dose for the Right Patient-Personalized Medicine Comes True Hong-Hao Zhou Institute of Clinical Pharmacology Pharmacogenetics