Safety and pharmacokinetic analysis of UGT1A1 genotype-guided dosing of irinotecan.
Authors: Hulshof Emma C. , de With Mirjam , de Man Femke M. , Creemers Geert-Jan , Deiman Birgit ALM , Swen Jesse J. , Houterman Saskia , Koolen Stijn L.W. , Laven Marjan , Luelmo Saskia , van Schaik Ron H.N. , Guchelaar Henk-jan , Mathijssen Ron H.J. , Gelderblom Hans , Deenen Maarten J. 
Published: June 2021

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Background: Irinotecan is commonly used in the treatment of advanced colorectal and pancreatic cancer. The polymorphisms UGT1A1*28 (7 TA repeats) and UGT1A1*93 (SNP -3156G > A) are significantly associated with increased systemic exposure of irinotecan’s active metabolite SN-38 and subsequently severe irinotecan-associated adverse-events (AEs) including (febrile) neutropenia and diarrhea. Severe AEs may lead to hospitalization, loss of quality of life, treatment delay and/or treatment discontinuation. Nonetheless, prospective genetic screening is not yet routinely performed. The aim of this study was to determine the safety and pharmacokinetics of UGT1A1 genotype-guided dosing of irinotecan in UGT1A1 poor metabolizers (PMs), i.e. UGT1A1 *28/*28 and/or UGT1A1*93/*93 individuals, in order to reduce the incidence of severe irinotecan-associated AEs. Methods: A prospective, multi-center, non-randomized study was conducted in patients intended to be treated with irinotecan at a dose of ≥ 180 mg/m2 or 450-600 mg flat dose. All patients were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1*93. In UGT1A1 PMs, an initial 30% dose reduction in the first cycle was applied followed by further individual dose titration based on neutrophil count and clinical tolerability. The primary endpoint was the incidence of febrile neutropenia in the first 2 cycles of irinotecan treatment. UGT1A1 PMs were compared to 1] historical control patients, i.e. homozygous polymorphic patients treated with full dose therapy identified from systematic literature review and to 2] UGT1A1 non-PMs treated with standard dose therapy. In addition, systemic SN-38 exposure (AUC0-500h) of reduced dosing in the UGT1A1 PM cohort was compared to a standard dosed irinotecan patient cohort [doi: 10.1200/JCO.2000.18.1.195] by an independent T-test. Results: A total of 349 patients were pre-therapeutically genotyped and included for analysis. Thirty-one (8.9%) patients were UGT1A1 PM, in whom an initial median 30% dose reduction was applied. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical controls (n = 50) (p = 0.042) and comparable with the incidence (4.1%; p = 0.632) in UGT1A1 non-PMs treated with full dose therapy. The systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs (n = 17) was comparable to the systemic exposure of the standard dosed irinotecan patient cohort (n = 46) with a relative difference of +24% (p = 0.054) with a geometric mean (CV) of SN-38 AUC0-500h of 391 (43.7%) versus 298 (75.3%) ng*h/mL, respectively. Conclusions: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan. In addition, systemic drug exposure remained adequate, despite the 30% dose reduction. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve the individual patient safety. Clinical trial information: Trial NL6270 (NTR6612).