Genomic Medicine and Personalized Treatment

Genomic Medicine and Personalized Treatment

• Genomic medicine studies how gene variations affect drug metabolism, predicting responses, minimizing side effects, enhancing treatment efficiency.
• Pharmacogenetics analyzes specific gene variants, while pharmacogenomics examines entire genome SNPs.
• Personalized/precision medicine applies pharmacogenetic findings to individual treatment plans.
• Lifestyle, diet, and environmental factors influence treatment effectiveness.

Targeted Therapy

• Targeted therapy uses monoclonal antibodies to target specific molecules in altered signal pathways of cancers.
• Trastuzumab (Herceptin) targets HER2neu gene amplification in breast cancer.
• Imatinib (Gleevec) targets receptor tyrosine kinases (e.g., c-KIT) for treatment of gastrointestinal stromal tumors (GIST) with c-KIT driver mutations and Philadelphia positive chronic myeloid leukemia.

Pharmacogenetic Testing

• Personalized medicine tests for genes impacting drug absorption, distribution, metabolism, and excretion (pharmacokinetics) and those related to drug action (pharmacodynamics).
• Genetic information controls all individual traits and affects both endogenous and exogenous (drug) metabolism.
• Most enzymatic reactions occur in the liver and genes for these enzymes are usually inherited in an autosomal recessive pattern.

Drug Metabolism and Pharmacokinetics

• Drugs undergo phase I metabolism (minor structural changes like removing functional groups, mainly cytochrome enzymes like CYP450) and phase II metabolism (complex enzymatic reactions, e.g., glutathione S-methyltransferase).
• Slow metabolizers have enzymes that detoxify drugs slower (reduced dosage needed), while rapid metabolizers have faster detoxification (increased dosage needed). Gene variations (SNPs) cause these differences.

Examples of Pharmacogenetics in Clinical Practice

• Thiopurines: Used to treat leukemia, metabolized by thiopurine S-methyltransferase (TPMT). TPMT*3 variant significantly reduces enzyme activity (lower dose needed; reduced dosage to 1/10).
• Citalopram: Antidepressant metabolized by CYP2D6. Variants like CYP2D6*9, #10, and #41 affect enzyme activity (adjust dose accordingly for reduced or increased function).
• Warfarin: Used for hypercoagulability, metabolized by CYP2C9. Certain CYP2C9 variants (e.g., *3, *2) severely reduce enzyme activity (warfarin levels carefully monitored). Warfarin inhibits vitamin K epoxide reductase (VKORCI); variants in this enzyme also influence treatment dosage to prevent bleeding. Vitamin K rich diet is a consideration for patients on Warfarin therapy.
• Allopurinol: Used for gout. HLA-B variants increase risk of severe Stevens-Johnson syndrome (genetic testing recommended).