Pharmacogenomics of Drug Disposition: From Polymorphisms to Biomarkers

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SELECTBIO

Interindividual variability in drug efficacy and toxicity is a major cause of therapeutic failure and contributes to high attrition rates during drug development. The recognition that part of this variation is inherited, and therefore predictable, created the field of pharmacogenetics in the 1950s. Genetic polymorphisms (i.e. common genetic variants of single genes) of enzymes for the metabolism of the antituberculosis drug isoniazid (N-acetyltransferase) and of the muscle relaxant succinylcholine (pseudocholinesterase) were the first examples. This was followed by numerous additional observations of genetic variation in drug disposition and in the 1980s with the elucidation of the molecular mechanisms at the gene level of these polymorphisms with the example of cytochrome P450 CYP2D6. Recent developments have broadened pharmacogenetic approaches to include multigenic, epigenetic, transcriptomic, proteomic and metabolomic information to describe phenotypic diversity and introduced the terms “pharmacogenomics” and “biomarkers” into the characterization of individual drug responses. It has been realized that the individuality of drug kinetics and response is caused by multiple factors including environmental and host factors in addition to the contribution of usually multiple gene variants. Examples of drug disposition which illustrate these concepts are tamoxifen in the treatment of breast cancer, statin myopathy, the toxicity of irinotecan and mercaptopurin, or the prediction of the individual dose of warfarin and clopidogrel.In the future, whole genome sequencing will provide the genetic components of drug response and systems pharmacology models will attempt to include the contribution of environmental and host factors. The reasonable hope is that this strategy will affect drug choice and drug dose and thereby decrease the number of adverse drug reactions and increase the efficacy of drug therapy.