Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, Meibergdreef 9, P.O. Box 22660, 1100 DD, Amsterdam, Netherlands.
Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
Eur J Clin Pharmacol. 2021 Aug;77(8):1193-1200. doi: 10.1007/s00228-021-03111-2. Epub 2021 Feb 24.
Pharmacokinetic (PK) differences between the extended half-life (EHL) factor IX (FIX) concentrates for hemophilia B exist, which may influence hemostatic efficacy of replacement therapy in patients. Therefore, we aimed to evaluate the PK properties of three EHL-FIX concentrates and compare them to a standard half-life (SHL) recombinant FIX (rFIX) concentrate.
Activity-time profiles of PEGylated FIX (N9-GP), FIX linked with human albumin (rIX-FP), FIX coupled to human IgG1 Fc-domain (rFIXFc), and SHL rFIX were simulated for 10,000 patients during steady-state dosing of 40 IU/kg once weekly (EHL-FIX) and biweekly (rFIX) using published concentrate specific population PK models.
Half-lives were respectively 80, 104, and 82 h for N9-GP, rIX-FP, and rFIXFc versus 22 h for rFIX. Between the EHL concentrates, exposure was different with area under the curve (AUC) values of 78.5, 49.6, and 12.1 IU/h/mL and time above FIX target values of 0.10 IU/mL of 168, 168, and 36 h for N9-GP, rIX-FP, and rFIXFc, respectively. N9-GP produced the highest median in vivo recovery value (1.70 IU/dL per IU/kg) compared with 1.18, 1.00, and 1.05 IU/dL per IU/kg for rIX-FP, rFIXFc, and rFIX, respectively.
When comparing EHL products, not only half-life but also exposure must be considered. In addition, variation in extravascular distribution of the FIX concentrates must be taken into account. This study provides insight into the different PK properties of these concentrates and may aid in determination of dosing regimens of EHL-FIX concentrates in real-life.
乙型血友病患者的延长半衰期（EHL）因子 IX（FIX）浓缩物之间存在药代动力学（PK）差异，这可能影响替代治疗的止血效果。因此，我们旨在评估三种 EHL-FIX 浓缩物的 PK 特性，并将其与标准半衰期（SHL）重组 FIX（rFIX）浓缩物进行比较。
使用已发表的浓缩物特异性群体 PK 模型，对 10000 名患者在每周一次（EHL-FIX）和每两周一次（rFIX）40IU/kg 稳态剂量下，模拟 PEGylated FIX（N9-GP）、与人白蛋白结合的 FIX（rIX-FP）、与人 IgG1 Fc 结构域结合的 FIX（rFIXFc）和 SHL rFIX 的活性时间曲线。
N9-GP、rIX-FP 和 rFIXFc 的半衰期分别为 80、104 和 82 小时，而 rFIX 的半衰期为 22 小时。在 EHL 浓缩物之间，暴露程度不同，N9-GP、rIX-FP 和 rFIXFc 的 AUC 值分别为 78.5、49.6 和 12.1IU/h/mL，FIX 目标值以上时间分别为 168、168 和 36h。与 rIX-FP、rFIXFc 和 rFIX 相比，N9-GP 产生的体内恢复中位数最高（每 IU/kg 1.70IU/dL），分别为 1.18、1.00 和 1.05IU/dL。
在比较 EHL 产品时，不仅要考虑半衰期，还要考虑暴露程度。此外，还必须考虑 FIX 浓缩物的血管外分布差异。本研究深入了解了这些浓缩物的不同 PK 特性，可能有助于确定 EHL-FIX 浓缩物在实际生活中的给药方案。
