Pharmacogenetics: Drug Response & Personalized Therapy PDF

PHARMACOLOGY PHAR 225 Suman Giri, M. Pharm 9/1/2024 1  Pharmacogenetics ❑ Genetics ▪ Study of heredity and its variations ❑ Genomics ▪ Study of the complete set of genetic information present in a cell, an organism, or species Suman Giri...

PHARMACOLOGY PHAR 225 Suman Giri, M. Pharm 9/1/2024 1  Pharmacogenetics ❑ Genetics ▪ Study of heredity and its variations ❑ Genomics ▪ Study of the complete set of genetic information present in a cell, an organism, or species Suman Giri 9/1/2024 2  Pharmacogenetics VS Pharmacogenomics ❑ Pharmacogenetics ▪ Study of how genes affect the way people response to drug therapy. ▪ Studies how variation in single gene influences the response to a drug. ▪ Aims to personalize drug treatments to improve efficacy and minimize adverse effects. ❑Pharmacogenomics ▪ Studies how all of the genes (genome) can influence responses to drugs. ▪ Study of variability in drug response determined by multiple genes within the genome. 9/1/2024 3  Factors Affecting Drug Response Suman Giri 9/1/2024 4  Pharmacogenetics Suman Giri 9/1/2024 5  Pharmacogenetics Suman Giri 9/1/2024 6  Genetic Polymorphism and Pharmacogenetics ▪ Genetic polymorphism refers to multiple differences of a DNA sequence found in at least 1% of the population resulting in variants of a gene sequence. ▪ Most common type of genetic variability is single nucleotide polymorphism (SNP) ▪ Genetic variation may result in altered protein sequence and function or in altered protein levels through regulatory variation. ▪ Key genes involved in driving variable drug actions include those encoding drug-metabolizing enzymes, drug transport molecules, the molecular targets with which drugs interact, can be critical determinants of variable drug responses. 9/1/2024 7  Genetic Polymorphism and Pharmacogenetics ▪ E.g. An effect occurs if nucleotide position 2935 of CYP2D6 gene has a ‘cytosine; C’ instead of an ‘adenine; A’ ▪ During translation of mRNA, this results in insertion of a amino acid “proline” instead of “histidine” at position 324 generating CYP2D6*7 allele which have no drug metabolizing activity. ▪ Since CYP2D6 is responsible for metabolism of various drugs, such genetic variability results in difference in metabolism of the same drug between individuals that results in difference in response of the drug. 9/1/2024 8  Genetic Polymorphism and Pharmacogenetics ▪ Moreover, if a genetic polymorphism leads to lower activity of a metabolizing enzyme, the plasma concentrations of the parent drug may increase whereas plasma concentrations of the metabolites declines. ▪ Hence, if only the parent drug exhibits pharmacological activity, genetic polymorphism will potentiate the drug response, including ADRs. ▪ However, if only the metabolites have the pharmacologic activity, genetic polymorphism may reduce the drug response. ▪ E.g. Tamoxifen and CYP2D6 polymorphisms ▪ Warfarin and CYP2C9 polymorphisms. Suman Giri 9/1/2024 9  Applications of Pharmacogenetics ❑ Drug Selection/Avoidance ▪ Who is at high risk of a serious ADR ▪ Who is not likely to respond to drugs ❑ Dose Optimization ▪ Who is likely to be sensitive or resistant to a drug ▪ What dose and what frequency of drug is needed to produce a desired therapeutic effect. Suman Giri 9/1/2024 10  Examples of Pharmacogenetics ▪ Warfarin, an anticoagulant is used to prevent blood clots. ▪ The effectiveness and safety of warfarin vary widely among patients, largely due to genetic differences in two key genes: CYP2C19 and VKORC1. ▪ Variations in these genes can affect how warfarin is metabolized and its impact on vitamin K recycling, which is crucial for its anticoagulant effect. ▪ Testing for these genetic markers helps tailor and optimize the warfarin dose to each patient's needs, reducing the risk of bleeding or clotting complications. Suman Giri 9/1/2024 11  Examples of Pharmacogenetics ▪ Clopidogrel, an antiplatelet medication requires activation by the CYP2C19 enzyme to be effective. ▪ Some people have genetic variants that reduce the enzyme's activity, leading to reduced drug effectiveness. ▪ Patients with these variants may need alternative medications or adjusted doses to achieve the desired therapeutic effect. Suman Giri 9/1/2024 12