Hulshof Emma C, de With Mirjam, de Man Femke M, Creemers Geert-Jan, Deiman Birgit A L M, Swen Jesse J, Houterman Saskia, Koolen Stijn L W, Bins Sander, Thijs Anna M J, Laven Marjan M J, Hövels Anke M, Luelmo Saskia A C, Houtsma Danny, Shulman Katerina, McLeod Howard L, van Schaik Ron H N, Guchelaar Henk-Jan, Mathijssen Ron H J, Gelderblom Hans, Deenen Maarten J
Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, the Netherlands; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands.
Department of Medical Oncology, Erasmus University Medical Centre, Rotterdam, the Netherlands; Department of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, the Netherlands.
Eur J Cancer. 2022 Feb;162:148-157. doi: 10.1016/j.ejca.2021.12.009. Epub 2022 Jan 5.
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.
确定基于UGT1A1基因分型指导的伊立替康给药的安全性、可行性、药代动力学及成本。
在这项前瞻性、多中心、非随机研究中，拟接受伊立替康治疗的患者在治疗前进行UGT1A1∗28和UGT1A1∗93基因分型。纯合变异携带者（UGT1A1慢代谢者；PMs）初始剂量降低30%。主要终点是治疗前两个周期发热性中性粒细胞减少的发生率。将UGT1A1 PMs的毒性与接受全剂量治疗的UGT1A1 PMs历史队列以及本研究中接受全剂量治疗的UGT1A1非PMs进行比较。次要终点是药代动力学、可行性和成本。
在350例可评估患者中，31例（8.9%）患者为UGT1A1 PMs，中位剂量降低30%。该组发热性中性粒细胞减少的发生率为6.5%，而历史上UGT1A1 PMs为24%（P = 0.04），与接受全剂量治疗的UGT1A1非PMs发生率相当。与标准剂量伊立替康患者队列相比，UGT1A1 PMs剂量降低时SN-38的全身暴露仍略高（差异：+32%）。成本分析表明，基于基因分型的给药具有成本效益，每位患者成本降低183欧元。
基于UGT1A1基因分型指导的给药显著降低了接受伊立替康治疗的UGT1A1 PM患者发热性中性粒细胞减少的发生率，产生了治疗有效的全身药物暴露，且具有成本效益。因此，为提高个体患者安全性，应考虑将基于UGT1A1基因分型指导的伊立替康给药作为标准治疗方案。
