Pharmacogenomics for Primary Care: An Overview

Abstract

Most of the prescribing and dispensing of medicines happens in primary care. Pharmacogenomics (PGx) is the study and clinical application of the role of genetic variation on drug response. Mounting evidence suggests PGx can improve the safety and/or efficacy of several medications commonly prescribed in primary care. However, implementation of PGx has generally been limited to a relatively few academic hospital centres, with little adoption in primary care. Despite this, many primary healthcare providers are optimistic about the role of PGx in their future practice. The increasing prevalence of direct-to-consumer genetic testing and primary care PGx studies herald the plausible gradual introduction of PGx into primary care and highlight the changes needed for optimal translation. In this article, the potential utility of PGx in primary care will be explored and on-going barriers to implementation discussed. The evidence base of several drug-gene pairs relevant to primary care will be outlined with a focus on antidepressants, codeine and tramadol, statins, clopidogrel, warfarin, metoprolol and allopurinol. This review is intended to provide both a general introduction to PGx with a more in-depth overview of elements relevant to primary care.

Keywords: adverse drug reaction; antidepressants; clopidogrel; drug hypersensitivity; implementation; pharmacogenomics; primary care; statins; warfarin.

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.

Figure 2

Four hypothetical pathways through which GPs may encounter pharmacogenetic tests within their primary care practice. Pathway 1 is where the GP initiates the test themselves; pathway 2 is where the genetic test is carried out in secondary care and the GP is informed of the test result; and pathway 3 is where the patient presents to the GP having undertaken a test privately or via a direct to consumer genetic testing laboratory. Pathways 1–3 represent situations where a single gene/variant test is undertaken for one gene-drug pair. Pathway 4 represents the situation where the patient has undergone a panel test or exome/whole genome sequencing, where there is the added complexity of storing the rest of the genetic data and having the ability to retrieve it, and use it appropriately in a pre-emptive fashion when a patient is prescribed a new drug(s).