Roche Pharma Research and Early Development, Pharmaceutical Sciences, Clinical Pharmacology, Roche Innovation Center Basel, Postfach, 4070, Basel, Switzerland.
Clin Pharmacokinet. 2020 Dec;59(12):1611-1625. doi: 10.1007/s40262-020-00904-z.
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.
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.
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.
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.
依库珠单抗是一种双特异性单克隆抗体，专为预防 A 型血友病患者（PwHA）出血而开发。本研究旨在描述依库珠单抗在成年和儿科 PwHA 中的药代动力学特征，确定导致其个体间变异性的因素，比较不同给药方案的药代动力学，并对暴露-出血事件关系进行描述性评估。
使用来自五项临床研究的 389 名 PwHA 的数据库，建立群体药代动力学模型。评估了潜在的基线协变量效应，包括体型、年龄、种族、VIII 因子抑制剂的存在和白蛋白水平。使用群体药代动力学模型，比较了不同年化出血率类别中个体在给药期间的估计平均暴露情况。
线性一室模型，具有一级吸收和消除过程，无滞后时间，可最佳描述依库珠单抗的药代动力学特征。体重、白蛋白水平、年龄和黑种人种族与主要药代动力学参数具有统计学相关性，但只有体重对暴露有重要影响。每周 1.5mg/kg、每 2 周 3mg/kg 或每 4 周 6mg/kg 的给药方案在稳态时提供相似的平均浓度。年化出血率>4（11.9%）的 PwHA 中观察到暴露水平较低的趋势，表明降低暴露水平可能会增加出血风险。
PwHA 中的依库珠单抗药代动力学特征与剂量无关，体重是依库珠单抗药代动力学的重要预测因素。所有三种给药方案预计均可实现相似的暴露，从而达到有临床意义的预防出血效果。
