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Pharmacogenetics: Integration into new drug development Academic Perspective

Pharmacogenetics: Integration into new drug development Academic Perspective. David Flockhart MD, PhD Indiana University School of Medicine . Steps Toward Clinical Pharmacogenetic Labelling. Response. Response. Genetic Variant No Yes.

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Pharmacogenetics: Integration into new drug development Academic Perspective

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  1. Pharmacogenetics: Integration into new drug developmentAcademic Perspective David Flockhart MD, PhD Indiana University School of Medicine

  2. Steps Toward Clinical Pharmacogenetic Labelling

  3. Response Response Genetic Variant No Yes

  4. Ideal Parameter Separation: Relative Risk is large RR Yes This Never Happens Response No No Yes Genetic Variant

  5. Number needed to test? Absolute Risk? Relative Risk? P < 0.05? Yes Response No No Yes Genetic Variant

  6. Genetically Polymorphic Cytochrome P450 Isoforms • CYP1A2 • CYP2B6 • CYP2C8 • CYP2C9 • CYP2C19 • CYP2D6 • CYP3A5

  7. 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

  8. CYP2D6 allele slide

  9. 120 1011 Subjects 80 Number of Subjects EMs PMs UMs 40 cutoff 0 0.01 0.1 1 10 100 Debrisoquine/4-Hydroxydebrisoquine Metabolic Ratio CYP2D6 Pharmacogenetics

  10. From: Eichelbaum et al: Pharmacogenetics 1997;8:15-26.

  11. 60 0 1 30 2 3 13 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

  12. Paroxetine : 1 deficient allele can distinguish from EMs Shin J-G et al: CPT 2000;67:567-576.

  13. Doses of nortriptyline recommended for different CYP2D6 phenotypes and genotypes in Europe.

  14. 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.

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