Page 61 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Introduction
DPWG guideline for DPYD and fluoropyrimidines
The role of heritable genetic variation on drug response is referred to as pharmacogenetics (PGx). Germline mutations in pharmacogenetic loci can predict phenotypic differences in drug response and can be used to guide dose and drug selection to achieve safer and more (cost)effective pharmacotherapy. PGx guided pharmacotherapy is one of the first clinical applications of genomics in medicine. Despite scientific and clinical advances in the field of PGx, clinical adoption has remained limited. Barriers preventing implementation have been previously reported.1 Some of these barriers have been overcome in the past years. One of these barriers was the lack of clear guidelines on how to interpret and apply PGx test results.
The Royal Dutch Pharmacists Association (KNMP) established the Dutch Pharmacogenetics Working Group (DPWG) in 2005 to overcome this barrier.2 The main objectives of the DPWG are 1) to develop PGx informed therapeutic recommendations based on systematic literature review, and 2) to assist physicians and pharmacists by integrating the recommendations into computerized systems for drug prescription, dispensing, and automated medication surveillance. This manuscript thus provides both the content required for enabling local translation of assay results into the predicted phenotype (in this case the gene activity score) and for programming therapeutic recommendations into local clinical decision support systems. With the objective of implementing PGx into routine care, the DPWG has additionally developed the clinical implication score, which is given to every gene- drug interaction. The aim of this score is to direct clinicians on whether or not to order relevant PGx genotyping tests before initiating therapy. Recently, the DPWG guidelines were endorsed by the European Association of Clinical Pharmacology and Therapeutics (EACPT) and the European Association of Hospital Pharmacists (EAHP).3,4Other initiatives such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) were also established to support clinical implementation.5,6
The DPWG is a multidisciplinary group in which (clinical) pharmacists, physicians, clinical pharmacologists, clinical chemists and epidemiologists are represented. From 2005 onwards, the DPWG has systematically executed 90 risk analyses for potential gene-drug interactions resulting in 49 guidelines providing therapeutic recommendations for one or more aberrant phenotypes.7 Available DPWG guidelines and future updates will be published in an effort to provide transparency of their development and to fulfil the public demand for their publication.
This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity; such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression. Dihydropyrimidine dehydrogenase enzyme (DPD) deficiency (which is encoded by the DPYD gene) increases the risk of fluoropyrimidine-induced toxicity. The gene activity score is currently based on the results of four DPYD variants, predicts DPD enzyme activity and is used to optimize an individual’s starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). This manuscript provides an overview of the guideline development and summarizes the pharmacotherapeutic recommendations. Additionally, a comparison to alternative guidelines is presented. The gene-drug interaction section includes background on the pharmacological mechanism of the interaction. In
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