Jin F, Robeson M, Zhou H, Hisoire G, Ramanathan S
Department of Clinical Pharmacology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
Department of Clinical Research, Gilead Sciences, Inc., Seattle, WA, USA.
Cancer Chemother Pharmacol. 2015 Dec;76(6):1133-41. doi: 10.1007/s00280-015-2898-1. Epub 2015 Nov 2.
Idelalisib is a novel, potent inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), which is prominently expressed in cells of hematopoietic origin. Renal excretion plays a minor role in elimination of idelalisib in humans (~15 % of the dose is excreted in urine). This study evaluated the pharmacokinetics (PK) and safety of idelalisib and GS-563117 (its inactive primary metabolite) in subjects with severe renal impairment and healthy subjects.
Subjects with severe renal impairment were matched in age, sex, and body mass index with healthy subjects who had normal renal function. Each subject received a single oral dose of idelalisib at 150 mg, and safety assessments and PK analyses were performed.
Compared with healthy subjects, the geometric least-squares mean ratio of area under the concentration-time curve from zero to last PK observation (AUC(last)), area under the concentration-time curve from zero to infinity (AUC(inf)), and maximum observed plasma concentration (C(max)) were 127, 127, and 105 % for idelalisib and 124, 124, and 96 % for GS-563117, respectively, in subjects with severe renal impairment.
There were no clinically relevant changes of idelalisib or GS-563117 PK in subjects with severe renal impairment versus matched healthy controls. No relevant relationships were identified between idelalisib or GS-563117 exposures and baseline creatinine clearance. Idelalisib dosing was generally well tolerated with most treatment-emergent adverse events and laboratory abnormalities assessed as grade 1 or 2 in severity. Accordingly, dose adjustments for idelalisib are not necessary in subjects with mild, moderate, or severe renal impairment.
idelalisib是一种新型、强效的磷脂酰肌醇3激酶δ（PI3Kδ）抑制剂，在造血来源的细胞中显著表达。肾脏排泄在idelalisib的人体消除过程中作用较小（约15%的剂量经尿液排泄）。本研究评估了idelalisib及其无活性主要代谢产物GS-563117在严重肾功能损害受试者和健康受试者中的药代动力学（PK）及安全性。
将严重肾功能损害受试者与肾功能正常的健康受试者按年龄、性别和体重指数进行匹配。每位受试者口服150mg单剂量的idelalisib，并进行安全性评估和PK分析。
与健康受试者相比，严重肾功能损害受试者中，idelalisib从零至最后一次PK观察的浓度-时间曲线下面积（AUC(last)）、从零至无穷大的浓度-时间曲线下面积（AUC(inf)）以及最大观察血浆浓度（C(max)）的几何最小二乘均值比分别为127%、127%和105%，GS-563117的相应比值分别为124%、124%和96%。
与匹配的健康对照相比，严重肾功能损害受试者中idelalisib或GS-563117的PK无临床相关变化。未发现idelalisib或GS-563117的暴露量与基线肌酐清除率之间存在相关关系。idelalisib给药一般耐受性良好，大多数治疗中出现的不良事件和实验室异常的严重程度评估为1级或2级。因此，轻度、中度或重度肾功能损害受试者无需调整idelalisib剂量。
