Tran Jonathan Q, Othman Ahmed A, Mikulskis Alvydas, Wolstencroft Paul, Elkins Jacob
Clinical Pharmacology, Biogen, Cambridge, MA, USA.
Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA; Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Clin Pharmacol. 2016 Feb 11;8:9-13. doi: 10.2147/CPAA.S98221. eCollection 2016.
Daclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the α subunit (CD25) of the high-affinity interleukin-2 receptor, has demonstrated efficacy for treatment of relapsing forms of multiple sclerosis in Phase II and III clinical trials.
To characterize the pharmacokinetics (PK) of DAC HYP following repeated administration of the 150 mg subcutaneous (SC) dose every 4 weeks (q4wk), the proposed clinical regimen in patients with relapsing-remitting multiple sclerosis (RRMS).
Twenty-six patients with RRMS received DAC HYP 150 mg SC q4wk for a total of six doses. Serial PK blood samples were collected over the first and last dosing intervals and trough PK samples were collected between these doses. Blood samples for immunogenicity assessment were collected throughout the study. Serum DAC HYP levels and anti-DAC HYP antibodies were characterized using validated immunoassays. PK parameters were estimated using noncompartmental analysis.
DAC HYP showed slow SC absorption with a median time to reach maximum observed concentration (Cmax) value of ~1 week. Steady state was reached by the fourth injection. At steady state, DAC HYP mean serum Cmax, minimum observed concentration (Cmin), and area under the concentration-time curve within a dosing interval (AUCtau) values were 29.1 µg/mL, 14.9 µg/mL, and 638 µg · day/mL, respectively, with intersubject variability of 35%-40%. The AUC accumulation ratio was ~2.5 at steady state. DAC HYP had a long elimination half-life of ~22 days and low apparent clearance (0.274 L/day). Nine patients tested positive for anti-DAC HYP antibodies, with no impact on DAC HYP clearance in this limited data set.
The PK of DAC HYP in patients with RRMS are consistent with those previously reported in healthy volunteers. The half-life of ~3 weeks and the low fluctuations in peak and trough concentrations of serum DAC HYP support the once-monthly SC dosing regimen.
达利珠单抗高产工艺（DAC HYP）是一种特异性针对高亲和力白细胞介素-2受体α亚基（CD25）的人源化免疫球蛋白G1单克隆抗体，已在II期和III期临床试验中证明对复发型多发性硬化症有效。
为了描述在复发缓解型多发性硬化症（RRMS）患者中按照建议的临床方案每4周（q4wk）皮下注射（SC）150mg剂量后DAC HYP的药代动力学（PK）特征。
26例RRMS患者接受每4周皮下注射DAC HYP 150mg，共六剂。在第一个和最后一个给药间隔期间采集系列PK血样，并在这些剂量之间采集谷值PK样本。在整个研究过程中采集用于免疫原性评估的血样。使用经过验证的免疫测定法对血清DAC HYP水平和抗DAC HYP抗体进行表征。使用非房室分析估计PK参数。
DAC HYP皮下吸收缓慢，达到最大观察浓度（Cmax）值的中位时间约为1周。第四次注射时达到稳态。在稳态时，DAC HYP的平均血清Cmax、最小观察浓度（Cmin）和给药间隔内浓度-时间曲线下面积（AUCtau）值分别为29.1μg/mL、14.9μg/mL和638μg·天/mL，受试者间变异性为35%-40%。稳态时AUC累积比约为2.5。DAC HYP的消除半衰期约为22天，表观清除率低（0.274L/天）。9例患者抗DAC HYP抗体检测呈阳性，在这个有限的数据集中对DAC HYP清除率没有影响。
RRMS患者中DAC HYP的PK与先前在健康志愿者中报道的一致。约3周的半衰期以及血清DAC HYP峰浓度和谷浓度的低波动支持每月一次的皮下给药方案。
