How to Consider Rare Genetic Variants in Personalized Drug Therapy

Personalized drug therapy aims to optimize the efficacy of pharmacological treatments by considering genetic, pathophysiological, dietary, and environmental factors as well as comedications and compliance. A multitude of associations between the specific genetic constitution of the patient and drug pharmacokinetics and pharmacodynamics has been identified in the last decades that encompass mainly common single nucleotide variants (SNVs) and gene copy number variations (CNVs) of importance for the function of genes encoding drug-metabolizing enzymes and transporters involved in drug absorption, distribution, metabolism, and excretion (ADME). In addition, genetic variation in factors encoding the major histocompatibility complex have been helpful to predict immune-mediated drug toxicity. This knowledge has been translated into clinical applications through the implementation of pharmacogenomic biomarkers. Over 230 of such markers that can, to a certain extent, predict drug efficacy or the likelihood of adverse drug reactions (ADRs) are recognized by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and are included in the drug labels of the respective medication. They are of particular value in cancer therapy to provide information of use to avoid ADRs and lack of response.