3 februari 2023: Bron: The Lancet

De dosering van medicijnen afstemmen op 12 genen van het DNA profiel van de patiënt blijkt voor 30 procent minder bijwerkingen te zorgen. 

In het internationale onderzoek onder leiding van het LUMC Leiden werd specifiek gekeken naar twaalf genen waarvan bekend is dat die invloed hebben op de werking van 39 verschillende medicijnen. Deze studie PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions (PREPARE) werd in de periode tussen 7 maart 2017 en 30 juni 2020 uitgevoerd bij 3342 patiënten die een genotypegestuurde medicamenteuze behandeling kregen en vergeleken met een controlegroep die standaardzorg kreeg (n=3602).  Ziekenhuizen uit zeven verschillende Europese landen deden mee aan deze studie.

Het ging om onder anderen patiënten die een medicatie tegen kanker, hartproblemen en psychische aandoeningen kregen. De patiënten begonnen allemaal met een medicijn waarvan bekend is dat de werking door de genen wordt beïnvloed.

Uit de resultaten blijkt dat patiënten met een behandeling gebaseerd op het DNA profiel mediaan 30 procent minder bijwerkingen vertoonden dan patiënten uit de controlegroep die de standaarddosis krijgen. Bijwerkingen die werden gemeld waren o.a. diarree, bloedarmoede, zenuwpijn en verlies van smaak.

  • 99 patiënten (52 [1,6%] van de onderzoeksgroep en 47 [1,3%] van de controlegroep trokken hun toestemming in na groepstoewijzing.
  • 652 deelnemers (367 [11,0%] in de onderzoeksgroep en 285 [7,9%] in de controlegroep) gingen verloren voor follow-up.
  • Bij patiënten met een bruikbaar testresultaat voor het indexgeneesmiddel (n=1558) trad een klinisch relevante bijwerking op bij 152 (21,0%) van de 725 patiënten in de onderzoeksgroep en bij 231 (27,7%) van de 833 patiënten in de controlegroep (odds ratio 0,70 [95% BI 0,54–0,91]; p=0,0075).
  • Terwijl voor alle patiënten de incidentie 628 (21,5%) van 2923 was patiënten in de studiegroep en 934 (28,6%) van 3270 patiënten in de controlegroep (OR 0,70 [95% BI 0,61–0,79]; p <0,0001).
Het volledige studierapport is tegen betaling in te zien of te downloaden. Hier het abstract van de studie zoals in The Lancet gepubliceerd:

Published:February 04, 2023DOI:https://doi.org/10.1016/S0140-6736(22)01841-4

Summary

Background

The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed.

Methods

We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug–gene interaction test result for which the Dutch Pharmacogenetics Working Group recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug–gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug–gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants.

Findings

Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio 0·70 [95% CI 0·54–0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61–0·79]; p <0·0001).

Interpretation

Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe.

Funding

European Union Horizon 2020.


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