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Pharmacogenomics and Personalized Medicine

• Pharmacogenomics studies how genetic variations affect drug responses. This includes predicting responses, minimizing side effects, and optimizing drug efficiency.
• Methods of analyzing these variations include multi-gene analysis (pharmacogenetics) or whole-genome SNP (Single Nucleotide Polymorphism) assays.
• Personalized medicine utilizes pharmacogenetic data to tailor treatment plans for individuals. Lifestyle, diet, and environment are also important factors.

Targeted Therapy

• Targeted therapy uses monoclonal antibodies to target specific molecules altered by genetic mutations in cancers. The example given is Trastuzumab (Herceptin) therapy targeting HER2 gene amplification in breast cancer.
• The ERBB2 gene (HER2) encodes a receptor tyrosine kinase, which is a protein that transmits signals within a cell.
• Imatinib (Gleevec) targets receptor tyrosine kinases, including KIT, often used to treat GIST (Gastrointestinal Stromal Tumors) with e-KIT driver mutations and Philadelphia positive chronic myeloid leukemia.

Pharmacogenetic Testing

• Pharmacogenetic testing focuses on genes involved in drug metabolism (pharmacokinetics) and drug targets (pharmacodynamics).
• Genes involved in drug metabolism often encode enzymes for absorption, distribution, metabolism, and excretion (ADME).
• Drug targets are proteins that the medication is designed to interact with.

Drug Metabolism

• Genetic information influences metabolism of both endogenous (within the body) and exogenous (from outside the body) substances, including medications.
• Most enzymatic reactions occur in the liver.
• Many genes encoding enzymes are inherited in an autosomal recessive pattern, but some are X-linked or, rarely, autosomal dominant.
• Drug metabolism has two phases: phase I and phase II.
  • Phase I metabolism often involves minor structural modification (e.g., removing hydroxyl or carboxyl groups) and is largely executed by cytochrome P450 (CYP) enzymes.
  • Phase II metabolism involves complex enzymatic reactions and results in a more active drug molecule using enzymes like glutathione S-methyltransferase (GST).

Drug Dose Adjustments Based on Metabolism

• Slow metabolizers express enzymes that metabolize drugs slowly, requiring lower doses to avoid side effects.
• Rapid metabolizers express enzymes that metabolize drugs quickly, necessitating higher doses for desired therapeutic effects.
• Polymorphisms (SNPs) in genes encoding these enzymes cause these differences in metabolism.

Examples in Clinical Practice

• Thiopurines (TPMT): Important for treating acute lymphoblastic leukemia, but can cause severe bone marrow suppression. A variant in the TPMT gene can dramatically reduce enzyme activity, necessitating lower doses, potentially to 1/10 of a normal dose, especially for individuals with homozygous mutations.
• Citalopram (CYP2D6): An antidepressant metabolized by CYP2D6. Variants affecting enzyme function (like CYP2D6*9, *10, *41) necessitate lower doses, while variants increasing activity require higher doses
• Warfarin (CYP2C9, VKORC1): Used for blood clot prevention (anticoagulation), metabolized by CYP2C9. Certain variants severely reduce CYP2C9 enzyme function, significantly affecting warfarin dosage. A variant in VKORC1 influences vitamin K synthesis, affecting warfarin dose and impact. Vitamin K-rich foods can influence warfarin dosage.
• Allopurinol (HLA-B): Used for treating gout; some variants in the HLA-B gene can significantly increase risk of severe adverse skin reactions (Stevens-Johnson syndrome) requiring testing before prescription. A high fatality rate is possible.