Diao Lei, Hang Yaming, Othman Ahmed A, Mehta Devangi, Amaravadi Lakshmi, Nestorov Ivan, Tran Jonathan Q
Janssen China R&D, Clinical Pharmacology, Shanghai, China.
Biogen, Cambridge, MA, 02142.
Br J Clin Pharmacol. 2016 Nov;82(5):1333-1342. doi: 10.1111/bcp.13051. Epub 2016 Aug 3.
Daclizumab high yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit of the interleukin-2 receptor and is being developed for treatment of multiple sclerosis (MS). This manuscript characterized the pharmacokinetic-pharmacodynamic (PK-PD) relationships of daclizumab HYP in subjects with MS.
Approximately 1400 subjects and 7000 PD measurements for each of three biomarkers [CD25 occupancy, CD56 natural killer (NK) cell count, regulatory T cell (Treg) count] from four clinical trials were analyzed using non-linear mixed effects modelling. Evaluated regimens included 150 or 300 mg subcutaneous (s.c.) every 4 weeks.
CD25 occupancy was characterized using a sigmoidal maximum response (E ) model. Upon daclizumab HYP treatment, CD25 saturation was rapid with complete saturation occurring after approximately 7 h and maintained when daclizumab HYP serum concentration was ≥5 mg l . After the last 150 mg s.c. dose, unoccupied CD25 returned to baseline levels in approximately 24 weeks, with daclizumab HYP serum concentration approximately ≤1 mgl 1L. CD56 NK cell expansion was characterized using an indirect response model. Following daclizumab HYP 150 mg s.c. every 4 weeks, expansion plateaus approximately at week 36, at which the average maximum expansion ratio is 5.2. After the last dose, CD56 NK cells gradually declined to baseline levels within 24 weeks. Treg reduction was characterized by a sigmoidal E model. Average maximum reduction of 60% occurred approximately 4 days post 150 mg s.c. dose. After the last dose, Tregs were projected to return to baseline levels in approximately 20 weeks.
Robust PK-PD models of CD25 occupancy, CD56 NK cell expansion and Treg reduction by daclizumab HYP were developed to characterize its key pharmacodynamic effects in the target patient population.
达克珠单抗高产工艺（HYP）是一种人源化IgG1单克隆抗体，可与白细胞介素-2受体的α亚基结合，目前正被开发用于治疗多发性硬化症（MS）。本手稿描述了达克珠单抗HYP在MS患者中的药代动力学-药效学（PK-PD）关系。
使用非线性混合效应模型分析了来自四项临床试验的约1400名受试者以及三种生物标志物[CD25占有率、CD56自然杀伤（NK）细胞计数、调节性T细胞（Treg）计数]各自约7000次的药效学测量数据。评估的给药方案包括每4周皮下注射（s.c.）150或300mg。
CD25占有率使用S型最大反应（Emax）模型进行描述。在达克珠单抗HYP治疗后，CD25饱和度迅速上升，约7小时后达到完全饱和，当达克珠单抗HYP血清浓度≥5mg/L时保持饱和状态。在最后一次皮下注射150mg剂量后，未被占据的CD25在约24周内恢复到基线水平，此时达克珠单抗HYP血清浓度约≤1mg/L。CD56 NK细胞扩增使用间接反应模型进行描述。每4周皮下注射150mg达克珠单抗HYP后，扩增在约第36周达到平台期，此时平均最大扩增率为5.2。在最后一剂后，CD56 NK细胞在24周内逐渐下降至基线水平。Treg减少使用S型Emax模型进行描述。皮下注射150mg剂量后约4天，平均最大减少率为60%。在最后一剂后，预计Treg在约20周内恢复到基线水平。
建立了达克珠单抗HYP对CD25占有率、CD56 NK细胞扩增和Treg减少的稳健PK-PD模型，以表征其在目标患者群体中的关键药效学作用。
