Diao Lei, Hang Yaming, Othman Ahmed A, Nestorov Ivan, Tran Jonathan Q
Clinical Pharmacology and Pharmacometrics, Biogen, Cambridge, MA, USA.
Janssen China R&D, Shanghai, China.
Clin Pharmacokinet. 2016 Aug;55(8):943-55. doi: 10.1007/s40262-016-0366-7.
Daclizumab high-yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit (CD25) of the interleukin-2 receptor. The present work characterized the population pharmacokinetics of daclizumab HYP in healthy volunteers (HVs) and subjects with relapsing-remitting multiple sclerosis (RRMS) and evaluated the effects of covariates on daclizumab HYP exposure.
Measurable serum concentrations (n = 17,139) from 1670 subjects in seven clinical studies (three phase I, one immunogenicity, one phase II with extension, and one phase III) were included in this pharmacokinetic analysis using non-linear mixed-effects modeling. The three phase I studies evaluated single or multiple doses that ranged from 50 to 400 mg with either intravenous or subcutaneous (SC) administration in HVs (n = 71). The phase II with extension studies evaluated doses of 150 or 300 mg SC every 4 weeks (n = 567), and the immunogenicity (n = 113) and the phase III (n = 919) studies evaluated 150 mg SC every 4 weeks, all in RRMS patients.
A two-compartment model with first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Clearance (CL) was 0.212 L/day and the central volume of distribution was 3.92 L, scaled by [body weight (kg)/68] with exponents of 0.87 and 1.12, respectively. The peripheral volume of distribution was 2.42 L. Absorption lag time, mean absorption time, and absolute bioavailability (100-300 mg SC) were 1.61 h, 7.2 days, and 88 %, respectively. The daclizumab HYP terminal half-life was 21 days. Baseline CD25, age, and sex did not influence daclizumab HYP pharmacokinetics. Body weight explained 37 and 27 % of the inter-individual variability for CL and central volume of distribution, respectively. Neutralizing antibody (NAb)-positive status (included as a time-varying covariate) increased daclizumab HYP CL by 19 %.
Consistent with previous findings in HVs, this analysis including extensive data from RRMS patients demonstrates that daclizumab HYP is characterized by slow CL, linear pharmacokinetics at doses above 100 mg, and high SC bioavailability. The pharmacokinetics of daclizumab HYP were not influenced by age (range 18-66 years), the sex of adult subjects, or the baseline CD4+CD25+ T cells (target level). The impact of covariates (body weight, NAb) on daclizumab HYP pharmacokinetics is unlikely to be clinically relevant.
达利珠单抗高产工艺（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（CD25）结合。本研究对达利珠单抗HYP在健康志愿者（HV）和复发缓解型多发性硬化症（RRMS）患者中的群体药代动力学进行了表征，并评估了协变量对达利珠单抗HYP暴露的影响。
本药代动力学分析使用非线性混合效应模型，纳入了七项临床研究（三项I期、一项免疫原性、一项II期扩展和一项III期）中1670名受试者的可测量血清浓度（n = 17,139）。三项I期研究评估了50至400 mg的单次或多次剂量，通过静脉注射或皮下（SC）给药，受试者为健康志愿者（n = 71）。II期扩展研究评估了每4周150或300 mg SC的剂量（n = 567），免疫原性研究（n = 113）和III期研究（n = 919）评估了每4周150 mg SC的剂量，所有研究对象均为RRMS患者。
具有一级吸收和消除的二室模型充分描述了达利珠单抗HYP的药代动力学。清除率（CL）为0.212 L/天，中央分布容积为3.92 L，分别按[体重（kg）/68]进行标化，指数分别为0.87和1.12。外周分布容积为2.42 L。吸收滞后时间、平均吸收时间和绝对生物利用度（100 - 300 mg SC）分别为1.61小时、7.2天和88%。达利珠单抗HYP的终末半衰期为21天。基线CD25、年龄和性别不影响达利珠单抗HYP的药代动力学。体重分别解释了CL和中央分布容积个体间变异性的37%和27%。中和抗体（NAb）阳性状态（作为时变协变量纳入）使达利珠单抗HYP的CL增加了19%。
与先前在健康志愿者中的研究结果一致，本分析包括来自RRMS患者的大量数据，表明达利珠单抗HYP的特点是清除缓慢、剂量高于100 mg时药代动力学呈线性以及皮下生物利用度高。达利珠单抗HYP的药代动力学不受年龄（18 - 66岁）、成年受试者性别或基线CD4 + CD25 + T细胞（靶水平）的影响。协变量（体重、NAb）对达利珠单抗HYP药代动力学的影响在临床上不太可能具有相关性。
