Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Department of Pediatric Hematology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
Eur J Clin Pharmacol. 2022 Feb;78(2):237-249. doi: 10.1007/s00228-021-03173-2. Epub 2021 Oct 15.
Hemophilia B is a bleeding disorder, caused by a factor IX (FIX) deficiency. Recently, FIX concentrates with extended half-life (EHL) have become available. Prophylactic dosing of EHL-FIX concentrates can be optimized by assessment of individual pharmacokinetic (PK) parameters. To determine these parameters, limited sampling strategies (LSSs) may be applied. The study aims to establish adequate LSSs for estimating individual PK parameters of EHL-FIX concentrates using in silico evaluation.
Monte Carlo simulations were performed to obtain FIX activity versus time profiles using published population PK models for N9-GP (Refixia), rFIXFc (Alprolix), and rIX-FP (Idelvion). Fourteen LSSs, containing three or four samples taken within 8 days after administration, were formulated. Bayesian analysis was applied to obtain estimates for clearance (CL), half-life (t), time to 1% (Time), and calculated weekly dose (Dose). Bias and precision of these estimates were assessed to determine which LSS was adequate.
For all PK parameters of N9-GP, rFIXFc and rIX-FP bias was generally acceptable (range: -5% to 5%). For N9-GP, precision of all parameters for all LSSs was acceptable (< 25%). For rFIXFc, precision was acceptable for CL and Time, except for t (range: 27.1% to 44.7%) and Dose (range: 12% to 29.4%). For rIX-FP, all LSSs showed acceptable bias and precision, except for Dose using LSS with the last sample taken on day 3 (LSS 6 and 10).
Best performing LSSs were LSS with samples taken at days 1, 5, 7, and 8 (N9-GP and rFIXFc) and at days 1, 4, 6, and 8 (rIX-FP), respectively.
血友病 B 是一种由凝血因子 IX（FIX）缺乏引起的出血性疾病。最近，具有延长半衰期（EHL）的 FIX 浓缩物已可获得。通过评估个体药代动力学（PK）参数，可以优化 EHL-FIX 浓缩物的预防性给药剂量。为了确定这些参数，可以应用有限采样策略（LSS）。本研究旨在通过计算机模拟评估，建立用于估计 EHL-FIX 浓缩物个体 PK 参数的合适 LSS。
使用已发表的 N9-GP（Refixia）、rFIXFc（Alprolix）和 rIX-FP（Idelvion）群体 PK 模型进行蒙特卡罗模拟，以获得 FIX 活性随时间的变化曲线。制定了 14 种 LSS，其中包含在给药后 8 天内采集的三个或四个样本。应用贝叶斯分析获得清除率（CL）、半衰期（t）、达到 1%的时间（Time）和计算的每周剂量（Dose）的估计值。评估这些估计值的偏差和精度，以确定哪种 LSS 是合适的。
对于 N9-GP、rFIXFc 和 rIX-FP 的所有 PK 参数，偏差通常可接受（范围：-5%至 5%）。对于 N9-GP，所有 LSS 的所有参数的精度均可接受（<25%）。对于 rFIXFc，CL 和 Time 的精度可接受，除了 t（范围：27.1%至 44.7%）和 Dose（范围：12%至 29.4%）。对于 rIX-FP，除了使用最后一个样本在第 3 天采集的 LSS（LSS 6 和 10）的 Dose 外，所有 LSS 均显示出可接受的偏差和精度。
表现最佳的 LSS 分别为在第 1、5、7 和 8 天采集样本的 LSS（N9-GP 和 rFIXFc）和在第 1、4、6 和 8 天采集样本的 LSS（rIX-FP）。
