What do we know?
There are not many studies that have demonstrated that genotype-guided drug prescription yields superior therapeutic results, but there are some. For example, studies have shown that reduced activity of the CYP2D6 enzyme results in reduced conversion of codeine to morphine. The consequence for the patient is less effective pain-relief. In a Caucasian population, about 10 % of patients who are prescribed codeine will experience the same pain-relief effect from codeine as from a placebo (7), i.e. over 3 500 patients in Norway in 2017 (8). Nonetheless, there are no routine checks for reduced CYP2D6 activity. The cost-benefit value has not been adequately determined for this indication. The price level for analysis of a sequence variant is currently NOK 146 (see the reimbursement rate to public laboratories of the Norwegian Health Economics Administration (Helfo)), and the number of sequence variants investigated per gene has a bearing on the overall price.
There is a widespread misconception that different variants of a CYP enzyme are of significance for all drugs metabolised by the enzyme in question. However, it is difficult to predict the consequences of genetic variants on pharmacokinetics and clinical end-points on the basis of theoretical considerations. If one metabolic pathway is disabled, other pathways may take over to a greater or lesser extent. A change in the metabolite pattern may also influence efficacy. For this reason, the test results cannot be used to guide treatment with a particular drug until the clinical significance of a genetic variant is actually documented for that drug.
The gold standard for documentation of clinical usefulness is randomised controlled trials, and ideally this documentation is required to change established treatment guidelines. Several studies have shown that stented patients with acute coronary disease and reduced CYP2C19 gene function are at greater risk of a further cardiovascular event when treated with clopidogrel than patients with normal CYP2C19 function (9). The influential medical community is somewhat reluctant to introduce pharmacogenetic testing as a standard of care, nonetheless, and there is a demand for an even stronger evidence base for recommending this to the patient population (10). Currently in progress in several European countries is a prospective randomised study aimed at evaluating the impact of pharmacogenetically guided prescription of 41 drug-gene pairs on clinical outcomes and cost-effectiveness. The initial results are expected in 2020 (11).
In some cases, evidence with less strength, such as pharmacokinetic studies or retrospective studies, may be sufficient. One such case concerns variants of the TPMT gene, which is associated with thiopurine toxicity. There are no large, prospective randomised clinical trials, and for ethical reasons it will not be possible to perform such trials on the basis of existing data, as treatment with standard doses of thiopurines of patients with two inactivating alleles of TPMT necessarily results in bone marrow suppression. Analysis of TPMT variants is currently being carried out on several patient groups for whom thiopurines are prescribed.
It can be difficult to translate genetic test results into clinical decisions. This was part of the background to the establishment in 2009 of the Clinical Pharmacogenetics Implementation Consortium, an international consortium whose purpose is to prepare the way for evidence-based use of pharmacogenetic analyses (4, 12). The consortium has published peer-reviewed dosing recommendations for gene-drug pairs where they find sufficient evidence for recommending a therapy based on genotype. The process of incorporating pharmacogenetic testing into clinical practice has come further in the USA than in Europe. Most large American hospitals that have implemented pharmacogenetics in clinical practice have chosen gene-drug pairs where such published therapeutic recommendations do exist (13). Examples of therapeutic areas for which recommendations exist are pain relief and treatment with proton pump inhibitors, antimycotics and antidepressants (6, 7, 14, 15).