UGT1A1 genotype-guided dosing of irinotecan: A prospective safety and cost analysis in poor metaboliser patients

• DOI: 10.1016/j.ejca.2021.12.009
• Publication Date: 2022-01-05T11:16:47Z
• Authors: Emma C. Hulshof; Mirjam de With; Femke M. de Man; Geert-Jan Creemers; Birgit A.L.M. Deiman; Jesse J. Swen; Saskia Houterman; Stijn L.W. Koolen; Sander Bins; Anna M.J. Thijs; Marjan M.J. Laven; Anke M. Hövels; Saskia A.C. Luelmo; Danny Houtsma; Katerina Shulman; Howard L. McLeod; Ron H.N. van Schaik; Henk-Jan Guchelaar; Ron H.J. Mathijssen; Hans Gelderblom; Maarten J. Deenen
• Keywords: Genotyping; Toxicity; Genotype; Irinotecan; 3. Good health; 03 medical and health sciences; UDP-glucuronosyl transferase; 0302 clinical medicine; SDG 3 - Good Health and Well-being; Pharmacogenetics; Costs and Cost Analysis; Humans; Camptothecin; Prospective Studies; Glucuronosyltransferase; UGT; Febrile Neutropenia

To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1∗28 and UGT1A1∗93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasibility, and costs.Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: +32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of €183 per patient.UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effective systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety.