Abstract：
Selumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low- and high-fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N-desmethyl selumetinib. The dataset comprised 511 subjects from 15 clinical trials who received ≥1 dose of selumetinib and provided ≥1 measurable postdose concentration of selumetinib and N-desmethyl selumetinib. A 2-compartment model with sequential 0- and 1st-order delayed absorption and 1st-order elimination adequately described selumetinib PK characteristics. A 1-compartment model reasonably described N-desmethyl selumetinib PK characteristics over time simultaneously with selumetinib. Selumetinib geometric mean area under the concentration-time curve ratio (1-sided 90% confidence interval [CI] lower bound) was 76.9% (73.3%) with a low-fat meal and 79.3% (76.3%) with a high-fat meal versus fasting. The lower bound of the 1-sided 90% CI demonstrated a difference of <30% between fed and fasted states. Considering the flat exposure-response relationship within the dose range (20-30 mg/m2), the observed range of exposure, and the variability in the SPRINT trial, this was not considered clinically relevant.
摘要：
Selumetinib在临床上用于患有1型神经纤维瘤病的儿科患者，不能手术的丛状神经纤维瘤。直到最近,司美替尼必须每天服用两次，禁食2小时后，然后禁食1小时，这可能很不方便。该人群分析评估了低脂和高脂膳食对司美替尼及其活性代谢物N-去甲基司美替尼的药代动力学（PK）参数的影响。数据集包括来自15项临床试验的511名受试者，他们接受≥1剂量的司美替尼，并提供≥1个可测量的司美替尼和N-去甲基司美替尼的剂量后浓度。具有顺序0和1阶延迟吸收和1阶消除的2室模型充分描述了司美替尼PK特征。1室模型合理地描述了N-去甲基司美替尼与司美替尼同时随时间的PK特征。Selumetinib浓度-时间曲线比（单侧90％置信区间[CI]下限）下的几何平均面积为76.9％（73.3％）低脂膳食和79.3％（76.3％）高脂膳食与禁食。单侧90%CI的下限表明在进食状态和禁食状态之间<30%的差异。考虑到剂量范围（20-30mg/m2）内的平坦暴露-响应关系，观察到的暴露范围，以及SPRINT试验中的变异性，这被认为没有临床相关性.
