Genetics Of Pharmacogenetics (PDF)

Precision and Personalized Medicine are frequently use interchangeably • Personalized medicine is a medical procedure that separates patients into different groups— with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted resp...

Precision and Personalized Medicine are frequently use interchangeably • Personalized medicine is a medical procedure that separates patients into different groups— with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted response or risk of disease. Personalized Medicine incorporates the idea of unique therapies for an individual. • Precision medicine is a medical model that proposes the customization of healthcare, with medical decisions, practices, or products being tailored to the individual patient who can be classified into a subgroup. Precision Medicine is an initiative of the US government. • Common to both • Each patient (and patient group) has a unique genetic/genomic makeup • The assessment, diagnosis, treatment and follow-up are unique to each individual because of genomic differences • Medicine is and always has been personal. We are all different. Precision Medicine adds genomic information to customize cancer treatment Precision Medicine Medicine has been becoming more personal Precision medicine started quite some time ago Precision Medicine Benefits Patients Pharmacogenomics/ Pharmacogenetics defined A new branch of Pharmacology which involves the study of the effects of genomic variations on drug response • The use of genetics/genomics measurements to make drug prescription decisions • Response or non-response • Side effect avoidance • Dose amount and timing decisions • The goal of pharmacogenetics/genomics is to maximize drug effectiveness while limiting drug toxicity, based on an individual's DNA. • Genetic information is routinely integrated into decisions regarding cancer chemotherapy and treatment for specific viruses and drug resistant infectious agents. Pharmacogenomics • Polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, and drug targets can influence drug effects and contribute to inter-individual differences in drug response. • Genotype for drug metabolizing enzymes and drug transporters can influence drug disposition in the body. • Genotype for drug targets may influence sensitivity to a drug. Target Half-life of drug determined by breakdown and excretion Stages of drug metabolism Examples of genotype driving medical decisions • Blood type • ABO blood group system is used to denote the presence of one, both, or neither of the A and B antigens on erythrocytes.– A, B, O • Transfusion compatibility decisions • Tissue typing • Tissue matching - typing antigens from the major histocompatibility complex (MHC) known as human leukocyte antigens (HLA) • A mismatch in MHC molecules between the donor and recipient can lead to graft rejection • Variations in MHC genes have been associated with susceptibility or resistance to various diseases Examples of genotype driving treatment decisions • HIV anti-viral treatment with Abacavir (Ziagen) • Patients with HLA-B variant (HLA-B *5701) have adverse reaction to drug • Methicillin-resistant Staphylococcus aureus (MRSA) infection is caused by a type of staph bacteria that's become resistant to many of the antibiotics used to treat ordinary staph infections. • Bacterial genotype makes it resistant to certain antibiotics, requiring another antibiotic to be prescribed Abacavir sensitivity frequency Treatment of ERpositive tumors often includes hormone therapy (tamoxifen) Breast cancer has 4 molecular subtypes Treatment of HER2- positive tumors often includes a monoclonal antibody that interferes with the HER2/neu receptor (Trastuzumab (Herceptin)) Examples of genotype driving medical decisions FDA Pharmaco- Herceptin genomic Erlotinib or Biomarkers Gefitinib More on in Drug CYP2D6 later Labeling ~500 drug biomarkers Examples of genotype driving medical decisions EGFR and Lung Cancer • Lung cancers that are EGFR-positive (following a biopsy anti-body test), can be treated with Gefitinib, Erlotinib that directly target EGFR • EGFR-positive tumors have a 60% response rate, which exceeds the response rate for conventional chemotherapy (often said to be 5%) • Gefitinib interrupts signaling by binding to the adenosine triphosphate (ATP)-binding site EGFR • Many patient’s tumors develop resistance to drug, i.e., their tumors acquire new mutations. EGFR co-crystallized with Gefitinib (PDB structure:1M17) Examples of genotype driving medical decisions Philadelphia chromosome and CML Gleevec - a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosomepositive (Ph+) chronic myelogenous leukemia (CML) Examples of genotype driving medical decisions Cytochrome P450 Enzymes • Cytochromes P450 (CYPs) are a superfamily of proteins that account for 75% of all drug metabolism • 57 Different active genes • 17 Different families • CYP1, CYP2 and CYP3 are primarily involved in drug metabolism. • CYP2A6, CYP2B6, CYP2C9 ,CYP2C19, CYP2D6, CYP2E1 and CYP3A4 are responsible for metabolizing most clinically important drugs Polymorphisms in CYP genes modify drug metabolism Codeine is a commonly used opioid Codeine is a prodrug -It must be metabolized into morphine for activity (pain relief) Cytochrome P450 gene, CYP2D6, is the metabolizing enzyme expressed in the liver Codeine Metabolism Genetics of Cytochrome P450 CYP2D6 Poor metabolizers – These patients have little or no working CYP2D6 Ultrarapid metabolizerPeople in this group have very high activity of CYP2D6 enzymes. https://www.pharmacytimes.com/view/2008-07-8624 Examples of genotype driving medical decisions Warfarin was originally used as a pesticide Warfarin (Coumadin) is an anticoagulant used to prevent thrombosis (blood clots) and thromboembolism (their migration). Commonly used to treat Atrial Fibrillation (effect, not cause) Warfarin’s use has evolved over time, and newer anticoagulant medications have become available as alternatives. Examples of genotype driving medical decisions: CYP2C9 Warfarin has significant complications • Previously ranked #1 in total mentions of deaths for drugs causing adverse events (from death certificates) • Ranks among the top drugs associated hospital emergency room visits for bleeding • Overall frequency of major bleeding range from 2% to 16% of patients • Minor bleeding event rates in randomized control trials of new anticoagulants has been as high as 29% per year. Finding Doses to Maintain Therapeutic Anticoagulation is Largely Trial and Error Warfarin Levels Depend on Two Enzymes – CYP2C9 & VKORC1 VKORC1 gene encodes the vitamin K epoxide reductase enzyme, and it is the target of warfarin. CYP2C9 modulates drug half life (excretion) vitamin K is essential for the synthesis of several clotting factors Estimated Warfarin Dose (mg/day) Based on Genotypes VKORC1, c.–1639G>A (rs9923231) variant is most studied but other VKORC1 variants may also be important determinants of warfarin dose. CYP2C9 alleles associated with warfarin dosage. CYP2C9 is highly polymorphic, with over 60 (*) alleles. Frequency of VKORC1 Alleles in Various Populations