Pharmacogenetics and the Promise
of Individualized Medical Care
John Deeken, M.D.
May 18, 2009
Pharmacogenomics
All patients with same diagnosis
Responders and
Patients not Experiencing
Severe Toxicity
Non-Responders and
Patients Experiencing
Severe Toxicity
Sources of Pharmacokinetic and
Pharmacodynamic Variability
Morphometric:
Body Size
Body Composition
Demographic:
Age
Race/Ethnicity
Sex
Physiologic:
Disease
Hepatic Function
Renal Function
Drug Specific:
Dose & Schedule
Dosage form
Genetics:
Variability
Environment:
Drug-drug interactions
Drug-CAM interactions
Drug-formulation interactions
Drug-food constituent interactions
Pharmacogenetics
Implications of polymorphisms
on Pharmacokinetics
• Drug Absorption
• Drug Distribution
• Drug Elimination
• Drug Metabolism
• Drug Activation
Implications of polymorphisms
on Drug Effect
• Receptors
• Target Proteins
Genetic Polymorphisms
Single Nucleotide Polymorphisms (SNPs)
 Non-synonymous and synonymous
 Upstream/downstream regulatory regions
 Copy number

Pharmacogenetics
Implications of polymorphisms
on Pharmacokinetics
• Drug Absorption
• Drug Distribution
• Drug Elimination
• Drug Metabolism
• Drug Activation
Implications of polymorphisms
on Drug Effect
• Receptors
• Target Proteins
Transporters Mediate Absorption
www.solvo.com
Transporters Mediate Bile
Elimination
www.solvo.com
Transporters Mediate Renal
Elimination
www.solvo.com
ABCG2 (BCRP, ATP-binding cassette)

Involved in intrinsic or acquired multidrug
resistance (MDR) phenotype of tumor cells

ABCG2 encodes a half transporter

Located on chromosome 4q-22

66 kb; 16 exons; 15 introns

69 Known genetic polymorphisms including 65
SNPs; 13 SNPs in exons; 7 SNPs cause amino acid
substitutions
Location of ABCG2 C421A and its functional
consequences
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
(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
Pharmacogenetics
Implications of polymorphisms
on Pharmacokinetics
• Drug Absorption
• Drug Distribution
• Drug Elimination
• Drug Metabolism
• Drug Activation
Implications of polymorphisms
on Drug Effect
• Receptors
• Target Proteins
Drug Metabolizing Enzymes
Evans and Relling, Science 286: 487-91, 1999
PGx of Drugs Used in Medical Oncology
Example of anticancer drug metabolism by polymorphic enzymes
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
Warfarin (Coumadin)

Name Your Poison
Warfarin (Coumadin)



Used for chronic anticoagulation
INR and lab testing
Two enantiomers (R- and S-)
Warfarin




Name Your Poison
Used for chronic anticoagulation
INR and lab testing
Two enantiomers, R and S
Warfarin
Metabolism
Importance of
CYP2C9
Warfarin
Pharmacodynamics
Importance of
VORC1
Warfarin -PGx


PGx: CYP2C9 and VORC1
Expert Committee Recommendation to FDA
Consider PGx testing, but needs further study
 Multiple studies currently ongoing, main U.S. study
funded by NIH
 Medicare announced May 4 that it will not pay for
genetic testing at this time


Will pay for genetic testing in clinical trials
PGx and Clopidogrel (Plavix)

Thienopyridine inhibitor of platelet P2Y12 ADP

Prodrug, requires activitation by CYP450
enzyme(s) and also inactivated by CYP450
enzyme(s) and other esterases

Much variability between patients in terms of
pK and PD (platelet aggregation)
PGx and Clopidogrel (Plavix)

Mega et al (NEJM Jan 22, 2009):



Pts with at least one reduced function variant in
CYP2C19:





healthy volunteers pK (n=162)
Cardiac patients on TRITON-TIMI study (n=1477)
32% reduction in active drug plasma levels
53% increase risk of death from CV causes, MI, or stroke
(12.1% vs 8.0%, HR 1.53)
Three-fold increased risk of stent thrombosis (2.6% v. 0.8%)
Caveat: research paid for by Eli Lilly and Daiichi Sankyo since
study was of prasugrel vs clopidogrel
FDA currently evaluating evidence to consider
requiring PGx testing before starting clopidogrel
Irinotecan (CPT-11)






Topoisomerase I inhibitor
Metabolized to active compound SN-38
Used in colon cancer
DLT – diarrhea
SN-38 inactivated by UGT1A1 glucoronidation
Polymorphism in UGT1A1 (UGT1A1*28) leads
to diminished inactivation, higher drug levels,
and higher toxicity
Mathijessen RHJ et al. Clin Cancer Res 2001:2168
Pharmacogenomics and Oncology:
New label for Irinotecan, July 2005:
FDA approved test in December, 2005
We still do not know what to do with dose
Pharmacogenetics
Implications of polymorphisms
on Pharmacokinetics
• Drug Absorption
• Drug Distribution
• Drug Elimination
• Drug Metabolism
• Drug Activation
Implications of polymorphisms
on Drug Effect
• Receptors
• Target Proteins
Tamoxifen




SERM
Used for adjuvant therapy in ER/PR+ breast CA
Metabolite Endoxifen is 100x more effective than
parent compound
CYP2D6 mediates activation of Tamoxifen to
Endoxifen
Tamoxifen
Importance of
CYP2D6
Pharmacogenetics
Implications of polymorphisms
on Pharmacokinetics
• Drug Absorption
• Drug Metabolism
• Drug Elimination
• Drug Distribution
• Drug Activation
Implications of polymorphisms
on Drug Effect
• Receptors
• Target Proteins
Beta Receptor and HTN/CHF





Beta blockers – well named
ADRB1 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 ACS
Pharmacogenetics
Implications of polymorphisms
on Pharmacokinetics
• Drug Absorption
• Drug Metabolism
• Drug Elimination
• Drug Distribution
• Drug Activation
Implications of polymorphisms
on Drug Effect
• Receptors
• Target Proteins
Pharmacogenomics and FDA
“Pharmacogenomics holds great promise to shed
scientific light on the often risky and costly process of
drug development, and to provide greater confidence
about the risks and benefits of drugs in specific
populations. Pharmacogenomics is a new field, but we
intend to do all we can to use it to promote the
development of medicines.”
-Mark McClennan, M.D.
FDA Commissioner Nov, 2003
Pharmacogenomics and FDA




2002: ‘Safe Harbor’ concept for data submissions
2003: Draft guidance for industry to submit genomic data
2004:
 PG identified as ‘Key opportunity’ in FDA’s ‘Critical Path’ for
the future
 Interdisciplinary PG Review Group Formed.
 First Voluntary Genomic Drug Submission (VGDS) received by
FDA
2005
 Genomics Website: www.fda.gov/cder/genomics
 Final rules published on guidance for industry
Pharmacogenomics - Industry

Biomarker/Genetic targets:
Abbott
Johnson & Johnson
Roche (Swiss)

Pharmacogenomics for individualized Rx:
Pfizer
Bristol-Myers-Squibb
Genentech

Molecular diagnostic kits/devices:
Roche expected sales this year: $6.5 billion
expected sales by 2010: $12 billion
Pharmacogenomics:
Industry
 First clinically available, FDA-approved genotype test in
2005 (Roche - Amplichip)
 Chip for SNPs in all CYP450 genes, 2005 (GE)
 Chip for p53 mutations expected mid-2006 (Roche)
 Affymetrix/ParAllele DMET Chip - 1,300 SNPs covering 185
genes (enzymes and transporters) involved in drug
metabolism Spring, 2006
Pharmacogenomics and NIH

Pharmacogenomics Research Network (PGRN)






Initiated based on NIH Scientific Advisory Panel
recommendation in 1999
Launched in year 2000
$140 million for first 5 years (UO1 mechanism)
12 centers funded from 2000 to 2005
Second 5-year period from 2005-2010, $150 million, again with
12 centers funded (not same as original)
NIGMS (General Medical Science) is lead NIH institute, with
other institutes participating, including NHLBI, NIDA, NCI,
NIEHS, NHGRI, NIMH, NLM, and ORWH
PGx – The Future of Individualized Medicine?
All patients with same diagnosis
Responders and
Patients not Experiencing
Severe Toxicity
Non-Responders and
Patients Experiencing
Severe Toxicity