Figure 1.

A summary of the mechanisms by which genomic variation can influence the pharmacokinetics and/or pharmacodynamics of a drug, with examples of clinically relevant drug-gene pairs. Genetic changes in drug-metabolising enzymes and transporters can alter a drug’s pharmacokinetics, influencing its tissue exposure and so affecting its downstream pharmacodynamics. These changes can lead to underexposure and potentially reduced effectiveness, or increase exposure predisposing often to type A (augmented) adverse drug reactions (ADRs), which are ADRs mediated through excessive action on the drug’s therapeutic target and so are predictable (e.g., bleeding after excessive warfarinisation). Secondly, genetic polymorphisms in a drug’s therapeutic target can directly modulate drug response, leading to reduced effectiveness or type A ADRs. Lastly, many small molecule drugs bind with varying affinities to unintended off-target molecules, both within and separate to the immune system. Genetic changes in these off-target sites can predispose to less predictable and less common type B (bizarre) ADRs. Of particular note, many rare but serious type B ADRs, such as drug-induced skin injury and drug-induced liver injury, are type IV T-cell mediated delayed type hypersensitivity reactions, and have been very strongly associated with specific human leukocyte antigen (HLA) alleles. It should also be noted that changes in a drug’s pharmacokinetics leading to increased exposure can, on occasion, predispose to off-target (type B) ADRs, as is the case, for example, with simvastatin myotoxicity.