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Hulshof, E.C.; With, M. de; Man, F.M. de; Creemers, G.J.; Deiman, B.A.L.M.; Swen, J.J.; ... ; Deenen, M.J. (2022)

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

Article / Letter to editor
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, feasi- bility, 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...Show moreAim: 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, feasi- bility, 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: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 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 effec- tive 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. (C) 2022 The Authors. Published by Elsevier Ltd.Show less
UDP-glucuronosyl transferase
UGT
Pharmacogenetics
Irinotecan
Genotyping
Toxicity
All authors
Hulshof, E.C.; With, M. de; Man, F.M. de; Creemers, G.J.; Deiman, B.A.L.M.; Swen, J.J.; Houterman, S.; Koolen, S.L.W.; Bins, S.; Thijs, A.M.J.; Laven, M.M.J.; Hovels, A.M.; Luelmo, S.A.C.; Houtsma, D.; Shulman, K.; McLeod, H.L.; Schaik, R.H.N. van; Guchelaar, H.J.; Mathijssen, R.H.J.; Gelderblom, H.; Deenen, M.J.
Date
2022-02-01
Journal
European Journal of Cancer
Volume
162
Pages
148 - 157
DOI
doi:10.1016/j.ejca.2021.12.009