Alternative Treatment Regimens With the PCSK9 Inhibitors Alirocumab and Evolocumab: A Pharmacokinetic and Pharmacodynamic Modeling Approach
Alternative Treatment Regimens With the PCSK9 Inhibitors Alirocumab and Evolocumab: A Pharmacokinetic and Pharmacodynamic Modeling Approach
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DOI：
10.1002/jcph.866
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发表时间：
2017-07
期刊：
影响因子：
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通讯作者：
N. Scherer;Christiane Dings;M. Böhm;U. Laufs;T. Lehr
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文献类型：
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作者：
N. Scherer;Christiane Dings;M. Böhm;U. Laufs;T. Lehr
Alibaba和evolocumab是2种人源单克隆抗体，可抑制前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）。这些抗体可有效降低低密度脂蛋白胆固醇（LDLc）血清浓度。本分析的目的是开发两种抗体的药代动力学（PK）和药效学（PD）模型，模拟和研究不同的剂量和应用方案，并最终记录对LDL c水平的影响。阿利坎特进行了临床研究，并批准了2种剂量，每2周75和150 mg（Q2 W），而evolocumab进行了测试，并批准了2个给药间隔，140 mg Q2 W和420 mg Q4 W。数据来自描述alirocumab和evolocumab PK以及各种单次和多次给药的人体LDLc水平的已发表研究。阿利司汀的剂量范围为75至300 mg，依洛司汀的剂量范围为7至420 mg。使用非线性混合效应建模技术进行分析。具有一级吸收和饱和消除的二房室模型最佳描述了两种抗体的PK。LDLc水平通过转换模型描述，其中零级合成速率因抗体而降低，一级降解速率因抗体而增加。模拟显示alirocumab 75 mg Q2 W和150 mg Q3 W以及evolucumab 140 mg Q2 W和420 mg Q5 W的有效性相当。这是第一个描述alirocumab和evolocumab PK和LDLc浓度之间联系的PK/PD模型。该模型可以作为一个重要的工具来模拟不同的剂量方案，以优化治疗。
Alirocumab and evolocumab are 2 human monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9). These antibodies can potently lower low‐density lipoprotein cholesterol (LDLc) serum concentrations. The aims of this analysis were to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for both antibodies, to simulate and investigate different dosage and application regimens, and finally, to note the effects on LDLc levels. Alirocumab was clinically studied and approved with 2 doses, 75 and 150 mg every 2 weeks (Q2W), whereas evolocumab was tested and approved with 2 dosing intervals, 140 mg Q2W and 420 mg Q4W. Data were digitized from published studies describing alirocumab and evolocumab PK, as well as LDLc levels in humans for various single and multiple doses. Alirocumab dosages ranged between 75 and 300 mg and evolocumab from 7 to 420 mg. The analysis was performed using a nonlinear mixed‐effects modeling technique. A 2‐compartment model with first‐order absorption and saturable elimination described the PK of both antibodies best. LDLc levels were described by a turnover model with zero‐order synthesis rate decreased by the antibodies and a first‐order degradation rate that was increased by the antibodies. Simulations show a comparable effectiveness for alirocumab 75 mg Q2W and 150 mg Q3W as well as evolucmab 140 mg Q2W and 420 mg Q5W, respectively. This is the first PK/PD model describing the link between alirocumab and evolocumab PK and LDLc concentrations. The model may serve as an important tool to simulate different dosage regimens in order to optimize therapy.