UGT1A1 genotype testing for irinotecan: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).
Irinotecan, a topoisomerase I inhibitor, is available as both non-pegylated and pegylated formulations. The non-pegylated formulation is licensed for use in advanced colorectal cancer either in combination with other agents or as monotherapy. However, it is also used off-label across a range of gastrointestinal malignancies and in rare malignancies such as glioblastoma and sarcomas. The pegylated formulation is licensed for use as combination therapy in adult patients with metastatic pancreatic adenocarcinoma. Irinotecan is hydrolysed to its active metabolite, SN-38, which is predominantly inactivated by the enzyme uridine diphosphate glucuronosyltransferase UGT1A1. UGT1A1 is encoded by the gene UGT1A1, which is polymorphically expressed, with allele frequencies varying across populations. Poor metabolizers carry two variants that reduce UGT1A1 enzyme expression or activity, leading to increased risk of irinotecan toxicity. Any patient who is about to be prescribed irinotecan for an epithelial malignancy should have pharmacogenetic testing, to identify clinically relevant UGT1A1 variants, where testing is available. Irinotecan dose should be reduced by 30% at Cycle 1 treatment in poor metabolizers for all indications, with doses titrated thereafter based on tolerability and neutrophil counts. The lack of evidence precludes us from making any recommendation for rare malignancies such as sarcomas. Our guideline is consistent with other international pharmacogenetics prescribing guidelines. This guideline is grounded in the latest evidence but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk-benefit profile, ensuring that therapy is optimized to maximize benefits while minimizing potential harms.