Division of Experimental Therapy and Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Br J Clin Pharmacol. 2013 Feb;75(2):507-15. doi: 10.1111/j.1365-2125.2012.04381.x.
Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours.
An open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m(-2) eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,∞) and C(max) for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (anova) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m(-2) eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed.
Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,∞) = 1.10, 90% CI 0.91, 1.34 and C(max) = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%).
These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.
盐酸伊立替康是一种新型紫杉烷类微管动力学抑制剂，最近被批准用于转移性乳腺癌的治疗。本研究旨在确定利福平（一种 CYP3A4 诱导剂）对转移性肿瘤患者体内盐酸伊立替康的药代动力学的影响。
进行了一项开放标签、非随机的 I 期研究。患者接受静脉注射 1.4mg/m²盐酸伊立替康，第 1 天和第 15 天，以及口服利福平 600mg，第 9 天至第 20 天，每 28 天为一个周期。在给药后最多 144 小时进行药代动力学采样，以确定盐酸伊立替康的血药浓度。无或有合用利福平时的盐酸伊立替康暴露的 AUC(0,∞)和 C(max)进行方差分析（anova），并计算相应的 90%置信区间（CI）。随后，允许患者继续接受伊立替康治疗，方案为每 21 天周期的第 1 天和第 8 天静脉注射 1.4mg/m²盐酸伊立替康。还评估了不良事件谱和抗肿瘤活性。
共纳入 14 例患者，其中 11 例患者可进行药代动力学分析。利福平合用对单次剂量的盐酸伊立替康暴露没有影响（几何均数最小二乘比值：AUC(0,∞)=1.10，90%CI 0.91，1.34和 C(max)=0.97，90%CI 0.81，1.17）。最常见的与治疗相关的≥3 级不良事件为 3/14（21%）的患者发生 3 级中性粒细胞减少症，3/14（21%）的患者发生白细胞减少症和疲劳。
这些结果表明，盐酸伊立替康可能与 CYP3A4 诱导剂安全合用。
