Pharmacogenetics: Integration into new drug development Academic Perspective

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Pharmacogenetics Integration into new drug
developmentAcademic Perspective

• David Flockhart MD, PhD
• Indiana University School of Medicine

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Steps Toward Clinical Pharmacogenetic Labelling
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Response
Response
Genetic Variant No Yes
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Ideal Parameter Separation Relative Risk is large
RR
Yes
This Never Happens
Response
No
No Yes
Genetic Variant
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Number needed to test?
Absolute Risk?
Relative Risk?
P lt 0.05?
Yes
Response
No
No Yes
Genetic Variant
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Genetically Polymorphic Cytochrome P450 Isoforms

• CYP1A2
• CYP2B6
• CYP2C8
• CYP2C9
• CYP2C19
• CYP2D6
• CYP3A5

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Cytochrome P450 2D6

• Absent in 7 of Caucasians
• Hyperactive in up to 30 of East Africans
• Catalyzes primary metabolism of
• codeine
• dextromethorphan
• metoprolol
• tamoxifen
• tricyclic antidepressants
• Inhibited by
• fluoxetine
• haloperidol
• paroxetine
• quinidine

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CYP2D6 allele slide
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CYP2D6 Pharmacogenetics
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From Eichelbaum et al Pharmacogenetics
1997815-26.
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Nortriptyline 2 allele patients had greater
clearance than 1 or 0 allele patients.
Number of functional CYP2D6 genes
Plasma concentration/25 mg dose (nmol/L)
0
0 24 48 72
Hours
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(No Transcript)
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Paroxetine 1 deficient allele can distinguish
from EMs
Shin J-G et al CPT 200067567-576.
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Doses of nortriptyline recommended for different
CYP2D6 phenotypes and genotypes in Europe.
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Recommendations

• Define and make clear a disease-specific
  parameter that is a target for a useful
  pharmacogenetic test.
• For CYP2D6, CYP2C19 and CYP2C9 recommend a
  genotype and phenotypic test that define the
  intermediate metabolizer group.