Northwell Health Cancer Institute, Lake Success, NY, USA.
University of California, Los Angeles, CA, USA.
Br J Clin Pharmacol. 2019 Jun;85(6):1239-1246. doi: 10.1111/bcp.13856. Epub 2019 Mar 28.
Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, nonrandomized study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations.
Patients aged ≥18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m orally twice daily on days 1-5 and 8-12 of each 28-day cycle.
Twenty-four patients were enrolled to the normal hepatic function (n = 8) and mild (n = 10) and moderate (n = 6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least 1 adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, 5 of 6 patients experienced grade ≥ 3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI area under the curve.
FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment.
替氟尿苷/盐酸拓扑替康（FTD/TPI）可延长难治性转移性结直肠癌患者的生存期，但有关其在肝功能受损患者中的应用数据有限。本Ⅰ期、开放性、非随机研究旨在调查 FTD/TPI 在晚期实体瘤（乳腺癌除外）和不同程度肝损伤患者中的安全性、耐受性和药代动力学特征，以提供剂量推荐。
计划招募年龄≥18 岁、患有晚期实体瘤且肝功能正常，或根据美国国家癌症研究所（NCI）标准为轻度、中度或重度肝功能损害的患者。患者接受 FTD/TPI 35mg/m2 口服，每日 2 次，第 1-5 天和第 8-12 天，每 28 天为一个周期。
共有 24 例患者分别入组肝功能正常（n=8）、轻度（n=10）和中度（n=6）肝损伤队列。总体而言，有 12 例患者（50.0%）至少发生了 1 次导致研究终止的不良事件。在中度肝损伤队列中，6 例患者中有 5 例出现胆红素升高≥3 级。未入组重度肝功能损害患者。FTD 稳态时的曲线下面积在轻度和中度肝损伤组中分别下降了 18%和 22%；然而，TPI 的曲线下面积未见明显变化。
FTD/TPI 可安全用于肝功能正常和轻度肝功能损害的患者，无需初始剂量调整。由于发现胆红素 3 级或 4 级升高，不建议 FTD/TPI 用于中度肝功能损害患者。因此，不建议中度或重度肝功能损害患者使用 FTD/TPI。
