Pharmacokinetics-Pharmacodynamics and Metabolism, Translational Medicine and Early Development, Sanofi R&D, Montpellier, France.
Pharmacokinetics and Pharmacometrics Department, School of Pharmacy, UFR Pharmacie, Montpellier University, 15 Avenue Charles Flahault, 34000, Montpellier, France.
Eur J Drug Metab Pharmacokinet. 2022 Nov;47(6):789-802. doi: 10.1007/s13318-022-00787-4. Epub 2022 Aug 16.
Alirocumab is a cholesterol-lowering monoclonal antibody targeting proprotein convertase subtilisin kexin type 9 (PCSK9) indicated in the prevention of cardiovascular risk and exhibiting target-mediated drug disposition (TMDD). The aim of this work was to develop an integrated pharmacokinetic-pharmacodynamic model to describe the interaction of alirocumab with PCSK9 and its impact on the evolution of low-density lipoprotein cholesterol (LDL-C) levels and explore labeling specification for subpopulations.
Using data collected from nine phase I/II/III clinical studies (n = 527, subcutaneous or intravenous administration), a TMDD model considering the quasi-steady-state approximation was developed to characterize the interaction dynamics of alirocumab and PCSK9, combined with an indirect pharmacodynamic model describing the inhibition of LDL-C by PCSK9 in a one-step approach using nonlinear-mixed effects modeling. A "full fixed effects modeling" strategy was implemented to quantify parameter-covariate relationships.
The model captures the interaction between alirocumab and its target PCSK9 and how this mechanism drives LDL-C depletion, with an estimation of the associated between-subject variability of model parameters and the quantification of clinically relevant parameter-covariate relationships. Co-administration of statins was found to increase the central volume of distribution of alirocumab by 1.75-fold (5.6 L versus 3.2 L) and allow for a 14% greater maximum lipid-lowering effect (88% versus 74%), highlighting the synergy of action between anti-PCSK9 therapeutic antibodies and statins toward lowering LDL-C plasma levels. Baseline levels of PCSK9 were found to be related to the amplitude of LDL-C variations by increasing the concentration of free PCSK9 necessary to reach half its capacity of inhibition of LDL-C degradation.
The maximum effect of alirocumab is achieved when free PCSK9 concentration is close to zero, as seen mostly after 150 mg every 2 weeks (Q2W) or 300 mg every 4 weeks (Q4W), indicating that there would be no additional clinical benefit of increasing the dose higher than these recommended dosing regimens.
阿利西尤单抗是一种针对前蛋白转化酶枯草溶菌素 9（PCSK9）的降胆固醇单克隆抗体，用于预防心血管风险，并表现出靶向介导的药物处置（TMDD）。本研究旨在开发一个综合药代动力学-药效学模型，以描述阿利西尤单抗与 PCSK9 的相互作用及其对低密度脂蛋白胆固醇（LDL-C）水平演变的影响，并探索亚人群的标签规范。
利用来自 9 项 I/II/III 期临床研究（n=527，皮下或静脉注射）的数据，开发了一个考虑准稳态近似的 TMDD 模型，以描述阿利西尤单抗和 PCSK9 的相互作用动力学，同时结合一个间接药效学模型，以一步法描述 PCSK9 对 LDL-C 的抑制作用，使用非线性混合效应建模。实施了“全固定效应建模”策略来量化参数-协变量关系。
该模型捕获了阿利西尤单抗与其靶标 PCSK9 之间的相互作用，以及这种机制如何驱动 LDL-C 的消耗，同时估计了模型参数的个体间变异性，并量化了临床相关的参数-协变量关系。发现他汀类药物的联合用药使阿利西尤单抗的中心分布容积增加了 1.75 倍（5.6 L 比 3.2 L），并使最大降脂效果增加了 14%（88%比 74%），突出了抗 PCSK9 治疗性抗体与他汀类药物联合降低 LDL-C 血浆水平的协同作用。PCSK9 的基线水平与 LDL-C 变化的幅度有关，通过增加达到其 LDL-C 降解抑制能力一半所需的游离 PCSK9 浓度来提高。
当游离 PCSK9 浓度接近零时，阿利西尤单抗的最大效应得以实现，这主要发生在每 2 周 150mg（Q2W）或每 4 周 300mg（Q4W）的剂量后，表明高于这些推荐剂量方案增加剂量不会带来额外的临床获益。
