Clinical Pharmacology and Early Development, CSL Behring, King of Prussia, PA, USA.
Global Clinical Research and Development, CSL Behring GmbH, Marburg, Germany.
J Thromb Haemost. 2017 Jun;15(6):1106-1114. doi: 10.1111/jth.13662. Epub 2017 Apr 21.
Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week.
Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for < 12 years) who had participated in a single-dose PK investigation with rVIII-SingleChain 50 IU kg . PK sampling was performed for up to 96 h. Results A two-compartment population PK model with first-order elimination adequately described FVIII activity. Body weight and predose level of von Willebrand factor were significant covariates on clearance, and body weight was a significant covariate on the central distribution volume. Simulations using the model with various dosing scenarios estimated that > 85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg ) and highest (50 IU kg ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios.
Essentials rVIII-SingleChain 是一种独特的重组凝血因子 VIII（FVIII）分子。基于重度 A 型血友病患者的 FVIII 活性，建立了群体药代动力学模型。该模型用于模拟各种给药方案的 FVIII 活性时间曲线。该模型支持间隔长达每周两次的 rVIII-SingleChain 延长给药。
单链重组凝血因子 VIII（rVIII-SingleChain）是一种独特的重组凝血因子 VIII 分子。目的：（i）描述重度 A 型血友病患者中 rVIII-SingleChain 的群体药代动力学（PK）特征；（ii）确定 rVIII-SingleChain PK 变异性的相关性；（iii）模拟 rVIII-SingleChain 的各种给药方案。
患者/方法：基于 130 名重度 A 型血友病患者（≥12-65 岁患者 n=91；<12 岁患者 n=39）单次 rVIII-SingleChain PK 研究的 FVIII 活性水平，建立了一个群体 PK 模型。PK 采样时间最长可达 96 小时。
FVIII 活性的一阶消除二室群体 PK 模型描述恰当。体重和 von Willebrand 因子的预剂量水平是清除率的显著协变量，体重是中央分布容积的显著协变量。使用具有各种给药方案的模型进行模拟，估计在最低（20IUkg）和最高（50IUkg）剂量下，所有年龄的患者在所有时间点都有>85%和>93%的患者被预测能维持 FVIII 活性水平>1IUdL，在三次每周给药（第 0、2 和 4.5 天）时，分别在最低（20IUkg）和最高（50IUkg）剂量下。对于每周两次（第 0 和 3.5 天）给予 50IUkg rVIII-SingleChain，在所有年龄的患者中，有 62-80%的患者在第 7 天被预测能维持 FVIII 活性水平>1IUdL。
该群体 PK 模型充分描述了 rVIII-SingleChain PK，可以用于模拟各种给药方案的 FVIII 活性时间曲线。
