Korth-Bradley Joan M, Rendo Pablo, Smith Lynne, Altisent Carmen
Pfizer, Collegeville, Pennsylvania.
Pfizer, Collegeville, Pennsylvania.
Clin Ther. 2016 Apr;38(4):936-44. doi: 10.1016/j.clinthera.2016.02.015. Epub 2016 Mar 8.
Nonacog alfa, a recombinant factor IX (FIX) product, is used for FIX replacement in the treatment and prevention of bleeding events in patients with hemophilia B. This study aimed to provide supplemental pharmacokinetic (PK), efficacy, and safety data for nonacog alfa when administered as part of usual hemophilia care, including on-demand treatment, routine prophylaxis, and surgical prophylaxis.
Men with previously treated severe or moderately severe hemophilia B (FIX activity ≤2%) were enrolled in this prospective, open-label, nonrandomized, multicenter study. An initial 72-hour PK assessment was performed wherein patients received a single dose of nonacog alfa (75 IU/kg) as an infusion over 10 minutes. A final 72-hour PK assessment was performed at the patient's last visit, after a minimum washout period of 4 days. Correlations between Cmax after the first dose and body weight and body mass index (BMI) were assessed post hoc using Spearman test after evaluating normality.
In total, 23 patients (age, 12-59 years; weight, 44-173 kg; and BMI, 16.3-45.1) with previous exposure to FIX products (median, 460 days; range, 150-2400 days) were enrolled; 21 were evaluable for efficacy. The median number of exposure days per efficacy-evaluable patient in this study was 48 (range, 31-103). The FIX activity profiles showed multiphasic disposition characteristics, with initial mean (SD) PK profiles as follows: Cmax, 61.4 (12.5) IU/dL; AUC∞, 1055 (227) IU·h/dL; t½, 23.7 (5.6) hours; and recovery, 0.818 (0.167) IU/dL. Mean plasma FIX activity versus time profiles were essentially identical upon initial exposure and after repeated use (n = 17), and bioequivalence was confirmed. No apparent relationship was observed between Cmax and either body weight (P > 0.1732) or BMI (P > 0.1235).
The FIX activity profile after administration of nonacog alfa is predictable and is not altered after repeated exposure during usual hemophilia care. PK parameters are consistent with nonacog alfa use for FIX replacement in on-demand treatment, routine prophylaxis, and surgical prophylaxis in patients with hemophilia B.
重组凝血因子IX产品诺那凝血素α用于替代凝血因子IX，以治疗和预防B型血友病患者的出血事件。本研究旨在提供诺那凝血素α作为常规血友病治疗一部分给药时的补充药代动力学（PK）、疗效和安全性数据，包括按需治疗、常规预防和手术预防。
既往接受过治疗的重度或中度重度B型血友病（凝血因子IX活性≤2%）男性患者纳入了这项前瞻性、开放标签、非随机、多中心研究。进行了初始72小时的PK评估，期间患者在10分钟内静脉输注单剂量诺那凝血素α（75 IU/kg）。在患者最后一次访视时进行了最终72小时的PK评估，经过至少4天的洗脱期。在评估正态性后，使用Spearman检验事后评估首剂后Cmax与体重和体重指数（BMI）之间的相关性。
总共纳入了23例曾接触过凝血因子IX产品（中位数460天；范围150 - 2400天）的患者（年龄12 - 59岁；体重44 - 173 kg；BMI 16.3 - 45.1）；21例可进行疗效评估。本研究中每例可评估疗效患者的暴露天数中位数为48天（范围31 - 103天）。凝血因子IX活性曲线显示多相处置特征，初始平均（标准差）PK曲线如下：Cmax为61.4（12.5）IU/dL；AUC∞为1055（227）IU·h/dL；t½为23.7（5.6）小时；回收率为0.818（0.167）IU/dL。初始暴露时和重复使用后（n = 17）的平均血浆凝血因子IX活性 - 时间曲线基本相同，确认了生物等效性。未观察到Cmax与体重（P > 0.1732）或BMI（P > 0.1235）之间存在明显关系。
诺那凝血素α给药后的凝血因子IX活性曲线是可预测的，在常规血友病治疗期间重复暴露后不会改变。PK参数与诺那凝血素α用于B型血友病患者按需治疗、常规预防和手术预防中的凝血因子IX替代一致。
