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

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 GelderblomMaarten J. Deenen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

Abstract

Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan. Patients and methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)148-157
Number of pages10
JournalEuropean Journal of Cancer
Volume162
Early online date5 Jan 2022
DOIs
Publication statusPublished - 1 Feb 2022

Bibliographical note

Funding Information:
This study was sponsored by the Catharina Research Foundation , Eindhoven, the Netherlands. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. ECH and MJD had full access to all the data in the study, and MJD had final responsibility for the decision to submit for publication.

Publisher Copyright:
© 2021 Elsevier Ltd

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