BACKGROUND:Emicizumab is a bispecific monoclonal antibody developed for routine prophylaxis of bleeding in people with hemophilia A (PwHA). This work characterizes the pharmacokinetics of emicizumab in adult and pediatric PwHA, identifies factors contributing to its between-person variabilities, compares the pharmacokinetics following different dosing regimens, and makes a descriptive assessment of the exposure-bleeding events relationship. METHODS:A population pharmacokinetic model was developed, using a database of 389 PwHA from five clinical studies. Potential baseline covariate effects were assessed, including body size, age, race, presence of factor VIII inhibitors, and albumin levels. Using the population pharmacokinetic model, the estimated individual average exposures over the administration period were compared across categories of annualized bleeding rate. RESULTS:A linear one-compartment model with first-order absorption and elimination processes and no lag time best described the emicizumab pharmacokinetics. Body weight, albumin levels, age, and black race were statistically correlated with primary pharmacokinetic parameters, but only body weight had an important influence on exposure. Dosing regimens of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks provided similar average concentrations at steady state. A trend for lower exposure was observed in the small proportion of PwHA having an annualized bleeding rate > 4 (11.9%), suggesting that reducing exposure to lower levels may potentially increase the bleeding risk. CONCLUSIONS:Emicizumab pharmacokinetics in PwHA was described with dose-independent parameters. Body weight was an important predictor of emicizumab pharmacokinetics. All three dosing regimens are predicted to achieve similar exposure associated with clinically meaningful prevention of bleeding.

译文

背景:艾米珠单抗是一种双特异性单克隆抗体,开发用于常规预防A型血友病(PwHA)出血。这项工作表征了艾米珠单抗在成人和儿科PwHA中的药代动力学,确定了导致其人际变异的因素,比较了不同给药方案后的药代动力学,并对暴露-出血事件之间的关系进行了描述性评估。
方法:使用来自五个临床研究的389 PwHA数据库建立了群体药代动力学模型。评估了潜在的基线协变量影响,包括体重,年龄,种族,VIII因子抑制剂的存在和白蛋白水平。使用总体药代动力学模型,比较了年平均出血率类别中估计的整个给药期间的个人平均暴露水平。
结果:具有一阶吸收和消除过程且无滞后时间的线性单室模型最能恰当地描述艾米珠单抗的药代动力学。体重,白蛋白水平,年龄和黑种人与主要药代动力学参数在统计学上相关,但仅体重对暴露有重要影响。每周1.5 mg / kg,每2周3 mg / kg或每4周6 mg / kg的给药方案在稳态下提供相似的平均浓度。在低比例的PwHA中观察到较低的暴露趋势,年出血率≥4(11.9%),这表明减少暴露于较低水平可能会增加出血风险。
结论:用剂量无关参数描述了艾美珠单抗在PwHA中的药代动力学。体重是艾米珠单抗药代动力学的重要预测指标。预计所有这三种给药方案都将实现与临床上有意义的出血预防相关的相似暴露。

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