Parmacogenetics in ICU patients: a short introduction

Abstract

Pharmacogenetics (PGx) studies the effect of genetic variation on drug response to tailor drug treatment to the individual patient’s needs. The clinical application of pharmacogenetic testing was mostly limited to investigate cases of an unexplained toxic drug response. For example, we reported a case of azathioprine overexposure in a newborn who was identified as a homozygous TPMT*3C genotype, which results in accumulation of 6-TGN, the active metabolite of azathioprine [1].While the application of retrospective testing remains useful in specific cases, the ultimate aim of pharmacogenetic testing is to apply our understanding of how genetic variation affects drug response and toxicity pre-emptively, informing precision therapeutic choices. Together, the Clinical Pharmacogenetic Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG) have published evidence-based guidelines for more than 100 gene–drug pairs [2]. Interestingly, the frequency of actionable variants commonly occur on a population level and 90–95% of individuals across multiple populations carry at least one actionable variant [3]. Moreover, the drugs covered in the guidelines are commonly prescribed, including antidepressants, anticoagulants, pain medication and chemotherapy, with an estimated ~ 25% of the individuals carrying an actionable variant relevant to the drugs they are using [4].The clinical utility of a pre-emptive pharmacogenetic panel strategy was recently tested in the PREPARE-study [5]. PREPARE was a prospective study that enrolled 6944 patients who started treatment with one of the 39 drugs that had an actionable recommendation in the DPWG. The results showed that pre-emptive application of the 12-gene PGx panel test combined with DPWG recommendations resulted in 30% lower risk for clinically relevant (grade 2–5 CTCAE) adverse drug reactions in the first 12 weeks after treatment initiation. Together with other available evidence these data provide a robust evidence base for a broader clinical application of pre-emptive pharmacogenetic testing [6].PGx testing is most likely to be clinically relevant for drugs with a narrow therapeutic index, a consistent PK-PD relationship and where it is difficult to predict response (or adverse effects) and little time is available for trial-and-error. Therefore, in addition to clinical fields where PGx is already well accepted (e.g. oncology and psychiatry) the intensive care unit (ICU), with complex patients receiving multiple drugs concomitantly, will also benefit from PGx testing.