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.