pharmacogenomics understanding the host and drug interface n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Pharmacogenomics: Understanding the Host and Drug Interface PowerPoint Presentation
Download Presentation
Pharmacogenomics: Understanding the Host and Drug Interface

Loading in 2 Seconds...

play fullscreen
1 / 110

Pharmacogenomics: Understanding the Host and Drug Interface - PowerPoint PPT Presentation


  • 103 Views
  • Uploaded on

Pharmacogenomics: Understanding the Host and Drug Interface. Stephen Becker. The Treatment Triad: Defining the Interfaces. Patient. Virus. Drug. The Treatment Triad: Defining the Interfaces. Patient. Virus. Drug. U.S. Drug Approval and Safety 1975-1999. Lasser, JAMA, 2002.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Pharmacogenomics: Understanding the Host and Drug Interface' - yakov


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
drug approval and safety 1975 1999
MAR 891_Becker_03Drug Approval and Safety 1975-1999
  • Drug categories with black box warning
    • Cardiovascular: 17
    • Antiviral agents: 6
    • Antineoplastics: 5
  • Drug categories of withdrawn agents
    • Analgesics/NSAIDs: 4
    • Cardiovascular: 4
    • Antihistamines: 2

Lasser, JAMA, 2002

drug metabolism mechanisms
MAR 891_Becker_03Drug Metabolism Mechanisms
  • Phase I Reactions: Cytochrome P450
  • Phase II Reactions: Conjugative enzyme systems
drug metabolism mechanisms1
MAR 891_Becker_03Drug Metabolism Mechanisms
  • Phase I Reactions: Cytochrome P450
    • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs
  • Phase II Reactions: Conjugative enzyme systems
drug metabolism mechanisms2
MAR 891_Becker_03Drug Metabolism Mechanisms
  • Phase I Reactions: Cytochrome P450
    • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs
    • Significant variability of 2D6 and 2C family
  • Phase II Reactions: Conjugative enzyme systems
drug metabolism mechanisms3
MAR 891_Becker_03Drug Metabolism Mechanisms
  • Phase I Reactions: Cytochrome P450
    • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs
    • Significant variability of 2D6 and 2C family
    • Levels of 3A4 may vary 60-fold in population
  • Phase II Reactions: Conjugative enzyme systems
drug metabolism mechanisms4
MAR 891_Becker_03Drug Metabolism Mechanisms
  • Phase I Reactions: Cytochrome P450
    • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs
    • Known variability of 2D6 and 2C family
    • Levels of 3A4 may vary 60-fold in population
  • Phase II Reactions: Conjugative enzyme systems
    • N-acetyltransferase (NAT) and INH neurotoxicity
drug metabolism mechanisms5
MAR 891_Becker_03Drug Metabolism Mechanisms
  • Phase I Reactions: Cytochrome P450
    • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs
    • Known variability of 2D6 and 2C family
    • Levels of 3A4 may vary 60-fold in population
  • Phase II Reactions: Conjugative enzyme systems
    • N-acetyltransferase (NAT) and INH neurotoxicity
    • Alcohol dehydrogenase, deficient in whites (5%), blacks (15%), Japanese (65%)
factors altering cyp450 function
MAR 891_Becker_03

Age

Gender

Race

Body mass index

Alcohol

Tobacco

Diet

Co-morbid conditions

Concomitant conditions

Altered organ function

Genetics

Factors Altering CYP450 Function
factors altering cyp450 function1
MAR 891_Becker_03

Age

Gender

Race

Body mass index

Alcohol

Tobacco

Diet

Co-morbid conditions

Concomitant conditions

Altered organ function

Genetics

Factors Altering CYP450 Function
factors altering cyp450 function2
MAR 891_Becker_03

Age

Gender

Race

Body mass index

Alcohol

Tobacco

Diet

Co-morbid conditions

Concomitant conditions

Altered organ function

Genetics

Factors Altering CYP450 Function
factors altering cyp450 function3
MAR 891_Becker_03

Age

Gender

Race

Body mass index

Alcohol

Tobacco

Diet

Co-morbid conditions

Concomitant conditions

Altered organ function

Genetics

Factors Altering CYP450 Function
factors altering cyp450 function4
MAR 891_Becker_03

Age

Gender

Race

Body mass index

Alcohol

Tobacco

Diet

Co-morbid conditions

Concomitant conditions

Altered organ function

Genetics

Factors Altering CYP450 Function
cyp 450 system
MAR 891_Becker_03CYP 450 System
  • CYP families 1-3
    • Catalyze xenobiotic compounds
  • CYP families > 4
    • Biosynthesis and degradation of hormones, signaling molecules and retinoic acid derivatives
cytochrome p450 nomenclature
MAR 891_Becker_03

Alleles

Cytochrome P450 Nomenclature

2C9*1*2

Family

Sub-family

Enzyme/gene

slide27
MAR 891_Becker_03

CYP Isoenzyme Systems

Substrate

slide28
MAR 891_Becker_03

CYP Isoenzyme Systems

Induction

Substrate

slide29
MAR 891_Becker_03

CYP Isoenzyme Systems

Induction

Substrate

X

Inhibition

slide30
MAR 891_Becker_03

3A4 Isoenzyme

Substrates

Benzos, statins

Oral contraceptives

Macrolides

HIV protease

inhibitors

slide31
MAR 891_Becker_03

3A4 Isoenzyme

Induction

Steroids

Phenobarb

Herbals

Rifamycins

Phenytoin

slide32
MAR 891_Becker_03

3A4 Isoenzyme

Induction

Inhibitors

Macrolides

Azoles

Ca+ blockers

Ritonavir

CSA

X

herbal and nutraceutical interactions with cyp450 3a4 isoenzyme
MAR 891_Becker_03Herbal and Nutraceutical Interactions with CYP450 3A4 Isoenzyme
  • Echinacea
  • Garlic pills
  • Grapefruit juice
  • Seville orange juice
  • Milk thistle
  • St. John’s wort
herbal and nutraceutical interactions with cyp450 3a4 isoenzyme1
MAR 891_Becker_03Herbal and Nutraceutical Interactions with CYP450 3A4 Isoenzyme
  • Echinacea
  • Garlic pills
  • Grapefruit juice
  • Seville orange juice
  • Milk thistle
  • St. John’s wort

Will alter the

metabolism of

substrates of

3A4 system.

Interactions

have clinical

significance

genetic determinants of metabolism and predicted clinical outcome
MAR 891_Becker_03

Poor Metabolizer

Ultra-Metabolizer

Multiple genes

Deleted gene

Diminished

Response

Normal Response

Toxicity

Genetic Determinants of Metabolism and Predicted Clinical Outcome
variability in enzymatic expression
MAR 891_Becker_03Variability in Enzymatic Expression

1000-fold

20-fold

Poor Metabolizer

Extensive Metabolizer

Normal Metabolizers

gender and pharmacology how little we know
MAR 891_Becker_03Gender and Pharmacology: How Little We Know
  • Pharmacology substudy of ACTG 359, n = 186
  • Measured SQV exposures. In females:
    • Clearance was 46% of that for males
    • AUC was therefore increased by 50%
    • Half-life prolonged by 50-100%

Brundage, CROI, 2002

drug metabolizing enzymes and allelic mutants
MAR 891_Becker_03Drug Metabolizing Enzymes and Allelic Mutants

Norweg,Ash Jews

Armenian

Chinese

New Guinean

Bantu, Ethiop,

Afro-Caribb

nelfinavir pharmacokinetics
MAR 891_Becker_03Nelfinavir Pharmacokinetics
  • Lag time in absorption, 1-2 hours
  • Circadian rhythm with AM troughs2 to 3-fold higher than PM levels
  • Active metabolite, M8
  • M8 felt to contribute to antiviral effect equal to parent compound
slide42
MAR 891_Becker_03

NFV and M8 Metabolism

3A4

NFV

2C19

M8

NFV

2D6

NFV

slide43
MAR 891_Becker_03

NFV and M8 Metabolism

3A4

M8

NFV

2C19

NFV

M8

2D6

NFV

slide44
MAR 891_Becker_03

NFV and M8 PK in the Settingof 2C19 Polymorphism

3A4

NFV

2C19

NFV

M8

2D6

NFV

m8 and nelfinavir levels by race ratio compared to pk population
MAR 891_Becker_03M8 and Nelfinavir Levels by Race(Ratio Compared to PK Population)

White

Black

Asian

NFV

1.07

1.17

1.23

M8

1.02

0.62

0.52

M8/NFV

Ratio

0.30

0.20

0.19

Baede-van Dijk, 2001

drug metabolizing enzymes and allelic mutants1
MAR 891_Becker_03Drug Metabolizing Enzymes and Allelic Mutants

Norweg,Ash Jews

Armenian

Chinese

New Guinean

Bantu, Ethiop,

Afro-Caribb

host determinants of response cellular efflux pumps1
MAR 891_Becker_03Host Determinants of Response:Cellular Efflux Pumps

OAT

OCT

MRP-1

ATP driven

Variability in

expression

and tissue

specificity

PGP

MRP-2

MRP-3

MRP-4

host determinants of response cellular efflux pumps2
MAR 891_Becker_03Host Determinants of Response:Cellular Efflux Pumps

OAT

OCT

MRP-1

ATP driven

Variability in

expression

and tissue

specificity

Xenobiotics

can act as

substrate,

inducer or inhibitor

PGP

MRP-2

MRP-3

MRP-4

p glycoprotein system
MAR 891_Becker_03P-glycoprotein System
  • Cellular counter transport system, partof host defense against xenobiotics
  • Product of mdr 1 gene associated withresistance to cancer chemotherapy
  • Primary expression in CNS, gut, genital tract, bone marrow, lymphocytes
  • Numerous drugs act as substrates, inducers or inhibitors of system
expression of p glycoprotein and genotype mdr1 3435
MAR 891_Becker_03Expression of P-glycoprotein and Genotype (MDR1 3435)

P-gp Genotype

P-gp Expression

T T

Reduced

C T

Normal

C C

Increased

Telenti. 2001.

p glycoprotein expression and response to haart
MAR 891_Becker_03P-glycoprotein Expression and Response to HAART
  • 123 patients treated with EFV or NFV containing regimens
  • All achieving HIV RNA < 400
  • Baseline CD4 and RNA levels equivalent
  • PCR techniques to characterize P-gp
  • Reported by Telenti at 41st ICAAC, published (Fellay), Lancet 2002
expression of p glycoprotein and genotype
MAR 891_Becker_03Expression of P-glycoprotein and Genotype

P-gp Genotype

P-gp Expression

T T

Reduced

C T

Normal

C C

Increased

Telenti. 2001.

expression of p glycoprotein and plasma drug levels
MAR 891_Becker_03Expression of P-glycoprotein and Plasma Drug Levels

P-gp Genotype

Plasma NFV or EFV

T T

30th percentile

C T

50th percentile

C C

75th percentile

Telenti. 2001.

expression of p glycoprotein and hiv response
MAR 891_Becker_03Expression of P-glycoprotein and HIV Response

P-gp Genotype

Change CD4 Count

T T

+ 257

C T

+ 165

C C

+ 121

Telenti. 2001.

p glycoprotein genotype and race
MAR 891_Becker_03P-glycoprotein Genotypeand Race

C C Genotype

Frequency

West Africans

80%

African Americans

80%

Whites

20%

defining race and ethnicity genotype vs phenotype
MAR 891_Becker_03Defining Race and Ethnicity: Genotype vs. Phenotype
  • Detailed chromosome microsatellite analysis
    • South African Bantu - Norwegians
    • Ashkenazi Jews - Armenians
    • Sichuan Chinese - Ethiopians
    • Papua New Guineans - Afro-Caribbeans

Wilson, Nature Genetics, 2001

defining race and ethnicity genotype vs phenotype1
MAR 891_Becker_03Defining Race and Ethnicity: Genotype vs. Phenotype
  • Four geographical areas
    • Sub-Saharan Africa
      • 96% Bantu
      • 79% Afro-Caribbeans
      • 24% Ethiopians
    • Western Eurasia
      • 95% Ashkenazi Jews
      • 95% Norwegians
      • 90% Armenians
      • 62% Ethiopians
      • 21% Afro-Caribbeans

Wilson, Nature Genetics, 2001

race and response to efavirenz conflicting datasets
MAR 891_Becker_03Race and Response to Efavirenz: Conflicting Datasets
  • Wegner (US Military HIV Research Program) evaluated time to virologic failure in 56 blacks, 43 whites
race and response to efavirenz conflicting datasets1
MAR 891_Becker_03Race and Response to Efavirenz: Conflicting Datasets
  • Wegner (US Military HIV Research Program) evaluated time to virologic failure in 56 blacks, 43 whites
    • TVF 1400 days for whites, 422 days for blacks (OR 2.42, CI 1.35-4.57, p=.0027)
race and response to efavirenz conflicting datasets2
MAR 891_Becker_03Race and Response to Efavirenz: Conflicting Datasets
  • Wegner (US Military HIV Research Program) evaluated time to virologic failure in 56 blacks, 43 whites
    • TVF 1400 days for whites, 422 days for blacks (OR 2.42, CI 1.35-4.57, p=.0027)
    • Comparison with NFV (n=172) or IDV (n=102) containing ART showed no difference in TVF
race and response to efavirenz conflicting datasets3
MAR 891_Becker_03Race and Response to Efavirenz: Conflicting Datasets
  • Wegner (US Military HIV Research Program) evaluated time to virologic failure in 56 blacks, 43 whites
    • TVF 1400 days for whites, 422 days for blacks (OR 2.42, CI 1.35-4.57, p=.0027)
    • Comparison with NFV (n=172) or IDV (n=102) containing ART showed no difference in TVF
    • Did not measure plasma EFV levels or characterize 2D6 alleles
race and response to efavirenz conflicting datasets4
MAR 891_Becker_03Race and Response to Efavirenz: Conflicting Datasets
  • DuPont 006 results
    • 170 black subjects enrolled
    • % attaining virologic success (< 50 copies) or those with virologic failure (> 50 copies) not different between blacks and whites
    • No difference when analyzed by as treated or intent to treat analysis

Besson, personal communication, 2002

race in medicine it s not racial profiling but genomic profiling1
MAR 891_Becker_03Race in Medicine: It’s Not Racial Profiling, But Genomic Profiling

“Skin color itself is not what is at issue -

it’s the evolutionary history indicated

by skin color”

Satel, New York Times, 2002

2 agonist receptor mutations and response to albuterol
MAR 891_Becker_03β-2 Agonist Receptor Mutations and Response to Albuterol

Israel, Am J Resp Crit Care Med, 2000; Israel, Int Arch Allergy Immunol, 2001

2 agonist receptor mutations and response to albuterol1
MAR 891_Becker_03β-2 Agonist Receptor Mutations and Response to Albuterol

Israel, Am J Resp Crit Care Med, 2000; Israel, Int Arch Allergy Immunol, 2001

leukotrienes and asthma
MAR 891_Becker_03Leukotrienes and Asthma
  • Three enzymes involved in formation of leukotrienes
leukotrienes and asthma1
MAR 891_Becker_03Leukotrienes and Asthma
  • Three enzymes involved in formation of leukotrienes
  • ALOX5 determines level of bronchoconstrictor leukotrienes in airways
leukotrienes and asthma2
MAR 891_Becker_03Leukotrienes and Asthma
  • Three enzymes involved in formation of leukotrienes
  • ALOX5 determines level of bronchoconstrictor leukotrienes in airways
  • Inhibition of ALOX5 action or antagonism of action of cysteinyl-leukotrienes at receptor is associated with bronchodilation
alox5 genotype and leukotreine inhibitor response
MAR 891_Becker_03ALOX5 Genotype and Leukotreine Inhibitor Response

+20

% Δ FEV1 from baseline

0

WT

Treated

WT

Placebo

Mutant

Treated

-10

Drazen, Nature Genetics, 1999

hypertension the adducin gene variant and the rate of mi or cva
MAR 891_Becker_03Hypertension: The α-Adducin Gene Variant and the Rate of MI or CVA
  • The G460T variant of the α-Adducin gene is associated with renal Na+ retention and salt-sensitive hypertension
  • Hypothesis: patients with variant allele treated with diuretic therapy would have lower rate of clinical events
  • Retrospective analysis of patients surviving MI or CVA
warfarin toxicity and cyp2c9 variability
MAR 891_Becker_03Warfarin Toxicity and CYP2C9 Variability
  • S-warfarin metabolized by 2C9
  • Wild type 2C9*1*1 present 68% population
  • Variant alleles *1*2 and *1*3 present 32%
warfarin toxicity and cyp2c9 variability1
MAR 891_Becker_03Warfarin Toxicity and CYP2C9 Variability
  • S-warfarin metabolized by 2C9
  • Wild type 2C9*1*1 present 68% population
  • Variant alleles *1*2 and *1*3 present 32%
    • *1*2 reduces enzyme activity ~ 30%
    • *1*3 reduces enzyme activity ~ 80%
warfarin toxicity and cyp2c9 variability clinical correlates
MAR 891_Becker_03Warfarin Toxicity and CYP2C9 Variability: Clinical Correlates

Warfarin maintenance dose (mg)

Higashi, JAMA, 2002

warfarin toxicity and cyp2c9 variability clinical correlates1
MAR 891_Becker_03Warfarin Toxicity and CYP2C9 Variability: Clinical Correlates

Warfarin maintenance dose (mg)

Higashi, JAMA, 2002

warfarin toxicity and cyp2c9 variability clinical correlates2
MAR 891_Becker_03Warfarin Toxicity and CYP2C9 Variability: Clinical Correlates

Events per 100 patient-years

Higashi, JAMA, 2002

warfarin toxicity and cyp2c9 variability clinical correlates3
MAR 891_Becker_03Warfarin Toxicity and CYP2C9 Variability: Clinical Correlates

Events per 100 patient-years

Higashi, JAMA, 2002

warfarin toxicity and cyp2c9 variability clinical correlates4
MAR 891_Becker_03Warfarin Toxicity and CYP2C9 Variability: Clinical Correlates

Events per 100 patient-years

Higashi, JAMA, 2002

abacavir hypersensitivity and the ancestral hla b 57 haplotype
MAR 891_Becker_03Abacavir Hypersensitivity and the Ancestral HLA-B*57 Haplotype
  • Mallal (W. Australia) studied 200 consecutive patients receiving ABC
    • Incidence HSR of 9%

Lancet,2002

abacavir hypersensitivity and the ancestral hla b 57 haplotype1
MAR 891_Becker_03Abacavir Hypersensitivity and the Ancestral HLA-B*57 Haplotype
  • Mallal (W. Australia) studied 200 consecutive patients receiving ABC
    • Incidence HSR of 9%
    • HLA-B*5701 present in 78% w/HSR, 2.3% with no HSR. Odds ratio = 117

Lancet,2002

abacavir hypersensitivity and the ancestral hla b 57 haplotype2
MAR 891_Becker_03Abacavir Hypersensitivity and the Ancestral HLA-B*57 Haplotype
  • Mallal (W. Australia) studied 200 consecutive patients receiving ABC
    • Incidence HSR of 9%
    • HLA-B*5701 present in 78% w/HSR, 2.3% w/no HSR. Odds ratio = 117
    • Additional loci of – DRB1*0701 and – DQ3 yielded OR = 73

Lancet,2002

abacavir hypersensitivity and the ancestral hla b 57 haplotype3
MAR 891_Becker_03Abacavir Hypersensitivity and the Ancestral HLA-B*57 Haplotype
  • Mallal (W. Australia) studied 200 consecutive patients receiving ABC
    • Incidence HSR of 9%
    • HLA-B*5701 present in 78% w/HSR, 2.3% w/no HSR. Odds ratio = 117
    • Additional loci of – DRB1*0701 and – DQ3 yielded OR = 73
    • Combining presence of two alleles, OR = 822

Lancet,2002

abacavir hypersensitivity and the ancestral hla b 57 haplotype4
MAR 891_Becker_03Abacavir Hypersensitivity and the Ancestral HLA-B*57 Haplotype
  • Hetherington (GlaxoSmith-Kline), 200 patients with matched controls
  • HLA-B*5701 present in 46% w/HSR, 3% with no HSR
  • Additional loci at promoter region of tumor necrosis factor (TNF)-alpha

CROI, 2002

the adme of pharmacology
MAR 891_Becker_03The ADME of Pharmacology

A = Absorption

D = Distribution

M =Metabolism

E = Excretion

the goal of pharmacogenomics
MAR 891_Becker_03The Goal of Pharmacogenomics
  • To understand the role that sequence variation among individuals and populations plays in the variability of response to drugs
the goal of pharmacogenomics1
MAR 891_Becker_03The Goal of Pharmacogenomics
  • To understand the role that sequence variation among individuals and populations plays in the variability of response to drugs
  • To determine the frequency and penetrance of sequence variants and their interaction with other genetic and environmental factors
use of pharmacogenomics to augment clinical response
MAR 891_Becker_03Use of Pharmacogenomics to Augment Clinical Response
  • Categorization of drug metabolizing enzymes (DMEs) and cellular efflux pumps to aid in selection of appropriate therapies
  • Use of selective DME or efflux pump inhibitors
use of pharmacogenomics in reducing adverse drug events
MAR 891_Becker_03Use of Pharmacogenomics in Reducing Adverse Drug Events
  • Modify drug selection or dosing in patients with poor expression or function of DMEs
  • Drug development that avoids metabolic pathways with common adverse genetic variability
  • Use of testing to identify genes known to confer risk of AEs
timeline of pharmacogenomics
MAR 891_Becker_03Timeline of Pharmacogenomics

1953 1956 1964 1990s 2010

INH neurotoxicty

due to NAT2

Elucidation of variant

alleles of P450 system, cellular efflux pumps, drug receptors

Phenytoin

hydroxylation

deficiency

G6PD

deficiency

pharmacotherapeutics today
MAR 891_Becker_03Pharmacotherapeutics: Today

Standard drug

and dose

Dose adjustment

for efficacy or toxicity

Decision for Rx

pharmacotherapeutics today and tomorrow
MAR 891_Becker_03Pharmacotherapeutics: Today and Tomorrow

Standard drug

and dose

Dose adjustment

for efficacy or toxicity

Decision for Rx

CYP and

efflux pump

genotyping

Decision for Rx

Drug and dose

selection