Hu Xiao, Hang Yaming, Cui Yue, Zhang Jie, Liu Shifang, Seddighzadeh Ali, Deykin Aaron, Nestorov Ivan
Biogen, Cambridge, MA, USA.
Gilead Sciences Inc, Cambridge, MA, USA.
J Clin Pharmacol. 2017 Aug;57(8):1005-1016. doi: 10.1002/jcph.883. Epub 2017 Apr 10.
Peginterferon beta-1a reduced annualized relapse rate as compared with placebo and was approved to treat multiple sclerosis patients. A population pharmacokinetic and an exposure-efficacy model were developed to establish the quantitative relationship between pharmacokinetics and annualized relapse rate. The pharmacokinetics was well described by a 1-compartment model with first-order absorption and linear elimination kinetics. Body mass index was the most significant covariate that impacted both clearance and volume of distribution, which in turn impacted area under the curve and maximum serum concentration. Cumulative monthly area under the curve and annualized relapse rate were best described by a Poisson-gamma (negative binomial) model, demonstrating that the improved efficacy of every-2-weeks dosing was driven by greater drug exposure. The results supported the superior efficacy of the every-2-week dosing regimen compared with the every-4-weeks dosing regimen.
与安慰剂相比，聚乙二醇干扰素β-1a降低了年化复发率，并被批准用于治疗多发性硬化症患者。建立了群体药代动力学和暴露-疗效模型，以确定药代动力学与年化复发率之间的定量关系。药代动力学通过具有一级吸收和线性消除动力学的单室模型得到很好的描述。体重指数是影响清除率和分布容积的最显著协变量，进而影响曲线下面积和血清最大浓度。曲线下面积的累积月值和年化复发率最好用泊松-伽马（负二项式）模型来描述，表明每两周给药一次疗效的提高是由更大的药物暴露驱动的。结果支持了每两周给药方案比每四周给药方案具有更高的疗效。
