Biogen Idec, 14 Cambridge Center, Cambridge, MA, 02142, USA.
Clin Pharmacokinet. 2014 May;53(5):467-77. doi: 10.1007/s40262-013-0129-7.
Recombinant factor IX Fc fusion protein (rFIXFc) is a clotting factor developed using monomeric Fc fusion technology to prolong the circulating half-life of factor IX. The objective of this analysis was to elucidate the pharmacokinetic characteristics of rFIXFc in patients with haemophilia B and identify covariates that affect rFIXFc disposition.
Population pharmacokinetic analysis using NONMEM(®) was performed with clinical data from two completed trials in previously treated patients with severe to moderate haemophilia B. Twelve patients from a phase 1/2a study and 123 patients from a registrational phase 3 study were included in this population analysis.
A three-compartment model was found to best describe the pharmacokinetics of rFIXFc. For a typical 73 kg patient, the clearance (CL), volume of the central compartment (V 1) and volume of distribution at steady state (V ss) were 2.39 dL/h, 71.4 dL and 198 dL, respectively. Because of repeat pharmacokinetic profiles at week 26 for patients in a subgroup, inclusion of inter-occasion variability (IOV) on CL and V 1 were evaluated and significantly improved the model. The magnitude of IOV on CL and V 1 were both low to moderate (<20 %) and less than the corresponding inter-individual variability. Body weight (BW) was found to be the only significant covariate for rFIXFc disposition. However, the impact of BW was limited, as the BW power exponents on CL and V 1 were 0.436 and 0.396, respectively.
This is the first population pharmacokinetic analysis that systematically characterized the pharmacokinetics of long-lasting rFIXFc in patients with haemophilia B. The population pharmacokinetic model for rFIXFc can be utilized to evaluate and optimize dosing regimens for the treatment of patients with haemophilia B.
重组凝血因子 IX Fc 融合蛋白（rFIXFc）是一种使用单体 Fc 融合技术开发的凝血因子，旨在延长因子 IX 的循环半衰期。本分析的目的是阐明接受过治疗的重度至中度血友病 B 患者中 rFIXFc 的药代动力学特征，并确定影响 rFIXFc 处置的协变量。
采用 NONMEM（®）进行群体药代动力学分析，分析来自两项已完成的针对既往接受过治疗的重度至中度血友病 B 患者的临床试验的临床数据。这项群体分析纳入了一项 1/2a 期研究中的 12 例患者和一项注册 3 期研究中的 123 例患者。
发现三房室模型最能描述 rFIXFc 的药代动力学。对于一名 73kg 的典型患者，清除率（CL）、中央室容积（V1）和稳态分布容积（Vss）分别为 2.39dL/h、71.4dL 和 198dL。由于亚组患者在第 26 周时有重复的药代动力学曲线，因此评估了 CL 和 V1 上的批间变异性（IOV）纳入对模型的影响，并显著改善了模型。CL 和 V1 上的 IOV 幅度均较低（<20%），且小于个体间变异性。体重（BW）被发现是 rFIXFc 处置的唯一显著协变量。然而，BW 的影响有限，因为 CL 和 V1 上的 BW 幂指数分别为 0.436 和 0.396。
这是首次对接受过治疗的血友病 B 患者中长效 rFIXFc 的药代动力学进行系统特征描述的群体药代动力学分析。rFIXFc 的群体药代动力学模型可用于评估和优化血友病 B 患者的治疗剂量方案。
