Personalised Therapeutics @ LUMC

Pharmacogenomics (PGx) is the study of genetic variability affecting an
individual*s response to a drug. PGx is a critical component of personalised
medicine. Currently, PGx is applied for individual drugs and/or individual
genetic variants. We recently proposed a pre-emptive panel-based approach
including 48 PGx variants covering 14 genes for which the Dutch Pharmacogenetic
Working Group (DPWG) has issued evidence based drug dosing guidelines. The PGx
panel contains all genetic variants that are considered actionable by the DPWG
i.e. requiring a dose adjustment or switch to another drug. Interestingly, more
than 95% of the Dutch population carries one or more actionable genotype(s) for
one of the genes covered by this panel and 10% carries 4 or more. Based upon
national prescription data we estimate that 5.6% of all first prescriptions
would require an individualization of the dose or drug. However, in current
clinical practice the potential of PGx testing is not fully exploited and the
impact for LUMC is unknown. Therefore a prospective study on pre-emptive PGx
testing will be performed in the LUMC.

To implement pre-emptive panel based PGx testing in the LUMC and determine
patient benefit of PGx guided drug prescription and dispensing.

A prospective, open, randomized study in 1,000 patients with a duration of 3
years.

Patients are randomised to PGx-guided dosing or standard of care. The PGx
guided group receives pre-emptive PGx testing for a panel of 14 genes
(including 260 PGx variants) followed by personalised drug and dose
recommendations for newly prescribed drugs. Recommendations are based on the
guidelines of the Dutch Pharmacogenetics Working Group. Patients in the control
group will receive usual drug prescriptions, without PGx-guided drug or dose
selection. Questionnaires will be used to investigate the results of the
intervention.

Substudies: We plan to conduct 3 sub-studies with the obtained data. The first
study aims to explore novel associations of genetic variants associated with
drug response. The second aims to explore the impact of concomitant medication
and other non-genetic factors on pharmacogenetic associations. The third aims
to test if an HLA risk allele panel test could be useful to identify people
vulnerable to drug hypersensitivity.

Patients are randomised to PGx-guided dosing or standard of care. The PGx
guided group receives pre-emptive PGx testing for a panel of 13 genes
(including 227 PGx variants) followed by personalised drug and dose
recommendations for newly prescribed drugs. Recommendations are based on the
guidelines of the Dutch Pharmacogenetics Working Group. Patients in the control
group will receive usual drug prescriptions, without PGx-guided drug or dose
selection.

Participation in this study carries a small extra burden:
1) 10 ml blood will be collected during a venipuncture. 2) to complete an
online questionnaires at one, three, six and twelve months. No extra visits to
the clinic are necessary. Benefits to patients in the study arm include a
potentially reduced risk of ADRs. All patients will receive their
pharmacogenetic profile which can be used to individualize drug treatment based
on the DPWG guidelines. Overall, minimal risks are expected for included
patients due to the fact that all of the drugs included within this study have
previously been licensed for routine use and thus have been evaluated as having
a positive benefit/risk ratio. The DPWG guidelines are based on systematic
review of the literature, have been published in peer-reviewed journals and are
commonly accepted.