Pharmacogenomics in personalized therapeutics: A comprehensive review of genetic determinants of drug response

Variability between different people when responding to drugs is a very large problem in clinical therapeutics, and can lead to treatment failures, adverse drug reactions, or under-dosing. Pharmacogenetics involves the study of the variation of one gene which affects a person's response to a single drug, while pharmacogenomics focuses on multiple genes and genome-wide variation on drug efficacy, safety, absorption, distribution, metabolism and excretion. These disciplines collectively serve as the building blocks of precision medicine and will allow for tailoring of drug therapy based on a person's genetic make-up. This review aims to offer a broad overview of the genetic determinants of drug variability, especially polymorphisms in drug metabolizing enzymes, such as the cytochrome P450 (CYP450) family, drug transporters and therapeutic target receptors. Pharmacogenomic markers of relevance to clinical practice are covered in the fields of oncology, cardiovascular diseases, psychiatry and pain management, with examples of how these markers can be incorporated into evidence-based guidelines with the help of organizations like the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the U.S. Food and Drug Administration (FDA). The review also provides space for some of the emerging new approaches for high throughput genotyping, next generation sequencing, and bioinformatics, which have been driving the incorporation of pharmacogenomic information into clinical decision making. In addition, important factors that hinder routine clinical use of the test, such as economic issues, ethnic variation in allele frequency, ethical issues, data privacy, and the lack of health care professional training, are described and critically discussed. Future trends in the area of individualized therapy are discussed of emerging developments in pharmacometabolomics, microbiome research, artificial intelligence, predictive analytics and polygenetic risk scoring. In summary, this review provides a summary of the current understanding, highlights the existing gaps in the field, and highlights the increasing translational relevance of pharmacogenetics and pharmacogenomics to enhance therapeutic efficacy and progress personalized medicine.