Personalized Medicine Approaches

Pharmacogenomics Fundamentals - Gene-Drug Dance

• Pharmacogenomics (PGx): Study of how genes influence individual drug responses. Core of personalized medicine.
• Key Genetic Variations:
  • Single Nucleotide Polymorphisms (SNPs)
  • Variations in genes for drug-metabolizing enzymes (e.g., CYP450), transporters, receptors.
• Impacts Drug Response:
  • Alters Pharmacokinetics (PK): Metabolism (e.g., poor vs. ultra-rapid metabolizers).
  • Alters Pharmacodynamics (PD): Drug target sensitivity.
• Clinical Goal: Optimize drug choice & dose; maximize efficacy, minimize Adverse Drug Reactions (ADRs).

⭐ Variations in CYP2D6 gene significantly affect metabolism of ~25% of all prescribed drugs, including opioids, antidepressants, and beta-blockers.

Key Genetic Variants - Code Red Response

• CYP2D6:
  • Poor Metabolizers (PMs): Codeine (ineffective), TCAs (↑ toxicity).
  • Ultrarapid Metabolizers (UMs): Codeine (↑ morphine, toxicity), some SSRIs (↓ efficacy).
• CYP2C19:
  • PMs: Clopidogrel (↓ activation, ↑ MACE risk).
• CYP2C9 & VKORC1:
  • Warfarin: Variants → ↓ metabolism/↑ sensitivity → ↑ bleeding. Dose ↓.
• TPMT & NUDT15:
  • Thiopurines (Azathioprine, 6-MP): Deficiency → severe myelosuppression. Test first.
• HLA Alleles:
  • HLA-B*57:01: Abacavir → fatal hypersensitivity. Screen!
  • HLA-B*15:02: Carbamazepine → SJS/TEN (Asians).
• DPYD:
  • 5-Fluorouracil/Capecitabine: DPD deficiency → severe toxicity.

⭐ HLA-B*57:01 screening is mandatory before initiating abacavir to prevent severe hypersensitivity reactions.

Pharmacogenomic Testing - Decoding Your Drugs

• Analyzes an individual's genetic makeup to predict their response to specific drugs.
• Aims for personalized medicine: optimizing drug choice & dosage, maximizing efficacy, minimizing adverse drug reactions (ADRs).
• Process:

• Common Tests:
  • CYP2C19: Clopidogrel efficacy.
  • TPMT/NUDT15: Thiopurine (e.g., azathioprine, 6-MP) toxicity.
  • HLA-B*57:01: Abacavir hypersensitivity.
  • SLCO1B1: Simvastatin-induced myopathy.

⭐ CYP2D6 genotyping is crucial for drugs like codeine (prodrug activated by CYP2D6) and tamoxifen. Poor metabolizers may experience ↓ efficacy, while ultra-rapid metabolizers risk ↑ toxicity.

Clinical PGx Examples - Tailored Treatments

• Warfarin: CYP2C9 (metabolism), VKORC1 (sensitivity) variants guide dosing.
  • *2/*3 alleles (CYP2C9), specific VKORC1 genotypes: ↓ dose to prevent bleeding.
• Clopidogrel: CYP2C19 (activation) variants affect efficacy.
  • *2/*3 alleles (poor metabolizers): ↓ active drug, ↑ MACE risk. Consider alternatives (prasugrel, ticagrelor).
• Abacavir (HIV): HLA-B*57:01 testing mandatory.
  • Positive status: Contraindicated (↑ severe hypersensitivity reaction risk).
• Carbamazepine: HLA-B*15:02 (Asians) associated with SJS/TEN. Test before initiating.

⭐ HLA-B*57:01 screening prior to abacavir initiation has significantly reduced life-threatening hypersensitivity reactions.

PGx: Indian Context - Desi Drug Destiny

• India's vast genetic diversity complicates PGx implementation.
• Focus areas: CYP2C19 (clopidogrel), TPMT (thiopurines), Warfarin (VKORC1, CYP2C9), HLA-B alleles.
• IndiGen Program: Building Indian population-specific genomic database.
• Challenges: High cost, limited access, regulatory gaps, ELSI.
• Goal: Optimize drug efficacy & safety for diverse Indian groups.

⭐ South Asians, including Indians, often carry CYP2C19 variants (e.g., *2, *3) leading to reduced clopidogrel activation.

High‑Yield Points - ⚡ Biggest Takeaways

• CYP2D6 polymorphisms alter metabolism of codeine, tamoxifen, and beta-blockers.
• CYP2C19 variants impact clopidogrel activation; poor metabolizers risk stent thrombosis.
• TPMT/NUDT15 testing is crucial before thiopurines (azathioprine) to prevent myelosuppression.
• HLA-B*5701 screening is mandatory before abacavir to avoid severe hypersensitivity reactions.
• Warfarin dosing considers CYP2C9/VKORC1 genotypes to optimize therapy and reduce bleeding.
• HER2/neu overexpression in breast cancer predicts response to trastuzumab therapy.