Ocular Half-Life of Intravitreal Biologics in Humans and Other Species: Meta-Analysis and Model-Based Prediction.,Molecular Pharmaceutics

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Ocular Half-Life of Intravitreal Biologics in Humans and Other Species: Meta-Analysis and Model-Based Prediction.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-12-26 , DOI: 10.1021/acs.molpharmaceut.9b01191
Antonello Caruso ₁ , Matthias Füth ₁ , Ruben Alvarez-Sánchez ₁ , Sara Belli ₁ , Cheikh Diack ₁ , Katie F Maass ₂ , Dietmar Schwab ₁ , Hubert Kettenberger ₃ , Norman A Mazer ₁

Affiliation

Therapeutic antibodies administered intravitreally are the current standard of care to treat retinal diseases. The ocular half-life (t1/2) is a key determinant of the duration of target suppression. To support the development of novel, longer-acting drugs, a reliable determination of t1/2 is needed together with an improved understanding of the factors that influence it. A model-based meta-analysis was conducted in humans and nonclinical species (rat, rabbit, monkey, and pig) to determine consensus values for the ocular t1/2 of IgG antibodies and Fab fragments. Results from multiple literature and in-house pharmacokinetic studies are presented within a mechanistic framework that assumes diffusion-controlled drug elimination from the vitreous. Our analysis shows, both theoretically and experimentally, that the ocular t1/2 increases in direct proportion to the product of the hydrodynamic radius of the macromolecule (3.0 nm for Fab and 5.0 nm for IgG) and the square of the radius of the vitreous globe, which varies approximately 24-fold from the rat to the human. Interspecies differences in the proportionality factors are observed and discussed in mechanistic terms. In addition, mathematical formulae are presented that allow prediction of the ocular t1/2 for molecules of interest. The utility of these formulae is successfully demonstrated in case studies of aflibercept, brolucizumab, and PEGylated Fabs, where the predicted ocular t1/2 values are found to be in reasonable agreement with the experimental data available for these molecules.

中文翻译：

玻璃体内生物制剂在人类和其他物种中的眼半衰期：荟萃分析和基于模型的预测。

玻璃体内给药的治疗性抗体是目前治疗视网膜疾病的护理标准。眼半衰期（t1 / 2）是靶标抑制持续时间的关键决定因素。为了支持新型，长效药物的开发，需要可靠地测定t1 / 2并加深对影响t1 / 2的因素的了解。在人和非临床物种（大鼠，兔，猴和猪）中进行了基于模型的荟萃分析，以确定IgG抗体和Fab片段的眼t1 / 2的共识值。在假设从玻璃体中扩散控制的药物消除的机制框架内，提供了多种文献和内部药代动力学研究的结果。我们的分析显示，从理论上和实验上，眼的t1 / 2与大分子的流体动力学半径（Fab的3.0 nm和IgG的5.0 nm）与玻璃球体半径的平方成正比，与玻璃体的半径成大约24倍成正比关系对人类的老鼠。种间比例因子间的差异是用机械学的术语观察和讨论的。此外，还提供了数学公式，可以预测感兴趣分子的眼t1 / 2。这些配方的实用性已在aflibercept，brolucizumab和PEG化Fab的案例研究中得到成功证明，其中预测的眼t1 / 2值与这些分子的可用实验数据合理地吻合。对于IgG为0 nm）和玻璃球半径的平方，从大鼠到人，其变化约为24倍。种间比例因子间的差异是用机械学的术语观察和讨论的。此外，提供了数学公式，可以预测感兴趣分子的眼t1 / 2。这些配方的实用性已在aflibercept，brolucizumab和PEG化Fab的案例研究中得到成功证明，其中预测的眼t1 / 2值与这些分子的可用实验数据合理地吻合。对于IgG为0 nm）和玻璃球半径的平方，从大鼠到人，其变化约为24倍。种间比例因子间的差异是用机械学的术语观察和讨论的。此外，提供了数学公式，可以预测感兴趣分子的眼t1 / 2。这些配方的实用性已在aflibercept，brolucizumab和PEG化Fab的案例研究中得到成功证明，其中预测的眼t1 / 2值与这些分子的可用实验数据合理地吻合。提出了数学公式，可以预测感兴趣分子的眼图t1 / 2。这些配方的实用性已在aflibercept，brolucizumab和PEG化Fab的案例研究中得到成功证明，其中预测的眼t1 / 2值与这些分子的可用实验数据合理地吻合。提出了数学公式，可以预测感兴趣分子的眼图t1 / 2。这些配方的实用性已在aflibercept，brolucizumab和PEG化Fab的案例研究中得到成功证明，其中预测的眼t1 / 2值与这些分子的可用实验数据合理地吻合。

更新日期：2020-01-17

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