Pharmacogenomics and Precision Medicine

PGx Fundamentals - Gene-Drug Dialogues

• Pharmacogenomics (PGx): How genes affect individual drug responses. Goal: optimize efficacy, minimize Adverse Drug Reactions (ADRs).
• Precision Medicine: Tailoring treatments to individual patient characteristics, including genetics, for better outcomes.
• Key Genetic Variations:
  • Single Nucleotide Polymorphisms (SNPs): Most common; single DNA base changes.
  • Copy Number Variations (CNVs): Altered gene copy numbers affecting protein levels.
• Mechanism: Genetic variants alter drug Absorption, Distribution, Metabolism, Excretion (ADME) & drug targets.

⭐ Variations in CYP450 genes (e.g., CYP2D6, CYP2C19) significantly impact metabolism of many common drugs, affecting efficacy and toxicity.

Enzyme Variants - Metabolic Modulators

• Genetic variants in drug-metabolizing enzymes (e.g., CYPs, TPMT, UGT1A1) cause interindividual differences in drug response.
• Metabolizer Phenotypes:
  • Poor (PM): Markedly ↓ enzyme activity.
  • Intermediate (IM): Moderately ↓ enzyme activity.
  • Extensive (EM): Normal enzyme activity (wild-type).
  • Ultrarapid (UM): Significantly ↑ enzyme activity due to gene duplication or activating variants.

• Clinical Implications & Examples:
  • PMs: Risk of ↑ drug toxicity (if parent drug is active) or ↓ efficacy (if drug is a prodrug requiring activation).
    • CYP2D6 & Codeine: PMs experience no analgesia (codeine is a prodrug).
    • TPMT & Thiopurines (azathioprine, 6-mercaptopurine): PMs face severe myelosuppression.
  • UMs: Risk of ↓ drug efficacy (active drug) or ↑ toxicity (prodrug).
    • CYP2D6 & Codeine: UMs risk morphine toxicity.
  • UGT1A1 & Irinotecan: UGT1A1*28 variant (Gilbert's syndrome) leads to ↑ irinotecan toxicity (neutropenia, diarrhea).

⭐ TPMT genetic testing is crucial before initiating thiopurines (e.g., azathioprine, 6-mercaptopurine) to prevent life-threatening myelosuppression in individuals with low or absent enzyme activity (PMs).

Transporters & Targets - Pathway Pilots

• Drug Transporters: Alter drug ADME.
  • SLCO1B1 (OATP1B1):
    • Hepatic uptake: Statins (simvastatin), methotrexate.
    • SLCO1B1*5 (c.521T>C): ↓ function → ↑ statin levels → ↑ myopathy risk. 📌 SLCO1B1 for Statins.
• Drug Targets/Receptors: Affect efficacy/toxicity.
  • VKORC1: Warfarin target. Variants (e.g., -1639G>A) → ↑ sensitivity → ↓ warfarin dose.
  • HER2 (ERBB2): Trastuzumab target. Overexpression in cancer predicts response.
  • HLA Alleles & Hypersensitivity:
    • HLA-B*57:01 + Abacavir → HSR. Screen.
    • HLA-B*15:02 + Carbamazepine/Phenytoin (Asians) → SJS/TEN. Screen.
    • HLA-A*31:01 + Carbamazepine → Hypersensitivity (various).

⭐ HLA-B*15:02 testing before carbamazepine in Asian populations is critical to prevent SJS/TEN.

Clinical PGx Apps - Bedside Gene Wisdom

Tailors drug therapy to genetics for ↑efficacy, ↓adverse drug reactions (ADRs).

• PGx Testing Process:

• Key Drug-Gene Pairs (Examples):
  • Clopidogrel & CYP2C19: Poor metabolizers (PMs) ↑ thrombotic event risk; consider alternatives.
  • Warfarin & CYP2C9/VKORC1: Variants impact dose; guide initial dosing.
  • Abacavir & HLA-B*57:01: Test all; avoid if positive (prevents hypersensitivity reaction - HSR).
  • Azathioprine & TPMT/NUDT15: ↓ enzyme activity ↑ myelosuppression risk; requires dose reduction.
• Strategies: Reactive (test upon ADR/inefficacy) vs. Pre-emptive (panel testing before first dose).
• Interpretation: Use clinical guidelines (e.g., CPIC, PharmGKB).
• ELSI (India): Cost, accessibility, data privacy, genetic counseling needs.

⭐ HLA-B*15:02 testing is mandatory/highly recommended before initiating carbamazepine in individuals of Asian ancestry to prevent Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN).

High‑Yield Points - ⚡ Biggest Takeaways

• CYP2D6 polymorphisms critically alter codeine efficacy and toxicity; CYP2C19 variants impact clopidogrel activation.
• TPMT and NUDT15 gene variants predict severe myelosuppression with thiopurines (e.g., azathioprine).
• Mandatory HLA-B*5701 screening prevents abacavir hypersensitivity reactions.
• Warfarin dosing is personalized using CYP2C9 (metabolism) and VKORC1 (target) genotyping.
• SLCO1B1 gene variants (OATP1B1 transporter) increase risk of statin-induced myopathy.
• HER2/neu testing directs trastuzumab therapy; EGFR mutations predict response to EGFR TKIs (Tyrosine Kinase Inhibitors).