1 | INTRODUCTION
Pharmacogenetics is the study of variability in drug responses associated with genetic differences amongst individuals. Drugs for which such variability in their effects has been linked to genetic polymorphisms are also referred to as pharmacogenetic (PGx) drugs [1].
Today, there is a growing list of PGx drugs, but the question of clinical relevance and implications of PGx test results in individual patients poses the next challenge. A widely accepted classification of the relevance of PGx testing for specific drug-gene pairs has been established by the Pharmacogenomics Knowledgebase (PHARMGKB). The three PHARMGKB categories with the highest level of evidence and clinical relevance for PGx-testing are termed “required”, “recommended” and “actionable”. Information from PHARMGKB is publicly available, continuously updated and based on expert opinions, published research studies, and PGx information from official Summary of Product Characteristics (SmPCs).
Until today, only few PGx drug-gene pairs fall into PHARMGKB’s “required” category based on the establishment of a very high attributable risk for (formerly) idiosyncratic, life-threatening adverse drug reactions (ADR) or lack of therapeutic efficacy and therefore a high predictive value of a detected PGx variant. For example, the association of severe skin reactions under abacavir and carbamazepine with genetic variations that code for human leucocyte antigens (HLA) fall into that category. After the establishment of sufficient evidence this information is now included in the labels of corresponding drugs, and PGx testing is mandatory before their first administration [2]. For drugs like e.g. the immunosuppressant azathioprine, PGx testing is not mandatory but classified as “recommended” to determine an effective and yet safe starting dose [3]. Other drug-gene pairs are currently only classified as “actionable”, in spite of a growing body of evidence on the strength of a clinically relevant association. Other factors such as lower costs and widespread availability of PGx-testing may further challenge their classification and promote a general recommendation of preemptive PGx testing for more drug-gene pairs in the future. Examples include prodrugs such as the platelet inhibitor clopidogrel, or tamoxifen for the secondary prevention of breast cancer [4-6].
PGx testing does not only promise to improve efficacy and safety outcomes for patients, it could also lead to overall savings in health care costs due to more efficient patient management strategies. Particularly preemptive PGx testing with multi-gene panels may have a high chance to identify clinically relevant variants. If they are used in a high number of subjects, costs of PGx testing may decrease considerably and therefore have a major impact on calculations that weigh costs vs. benefits.
Despite many potential benefits, the implementation of PGx testing in clinical practice remains a slow process, particularly outside academic hospitals. Challenges include limited and sometimes controversial evidence with regard to improved clinical outcomes for many drug-gene pairs [7], discrepancies between guidelines from PGx expert groups vs. different medical specialty associations [6, 8, 9], reaction time of regulatory authorities regarding the implementation of new PGx evidence, and limited reimbursement of the costs for PGx tests [10, 11]. Furthermore, even if a valid PGx test is performed, it may be challenging to find an expert who can interpret its findings and manage pharmacotherapy within a patient’s individual clinical context [12]. Clinical PGx experts must not only consider interactions for one or several drug-gene pairs, but also many other relevant cofactors such as age, comorbidities, comedication and patients’ personal perceptions of risks and benefits.
Therefore, the utility of PGx as a guiding tool for pharmacotherapy in clinical practice is subject to ongoing studies and controversial debates. There is still limited data on the implementation of PGx services in routine clinical practice and subsequent PGx-based changes in medication management. Therefore, the present study describes our experience from the implementation and interpretation of a PGx panel test, and its relevance for the management of current and future pharmacotherapy in individual patients.