Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York, University at Buffalo 455 Kapoor Hall, Buffalo, NY, 14214-8033, USA.
J Pharmacokinet Pharmacodyn. 2024 Oct;51(5):493-508. doi: 10.1007/s10928-023-09881-9. Epub 2023 Aug 9.
We have previously published a PBPK model comprising the ocular compartment to characterize the disposition of monoclonal antibodies (mAbs) in rabbits. While rabbits are commonly used preclinical species in ocular research, non-human primates (NHPs) have the most phylogenetic resemblance to humans including the presence of macula in the eyes as well as higher sequence homology. However, their use in ocular research is limited due to the strict ethical guidelines. Similarly, in humans the ocular samples cannot be collected except for the tapping of aqueous humor (AH). Therefore, we have translated this rabbit model to monkeys and human species using literature-reported datasets. Parameters describing the tissue volumes, physiological flows, and FcRn-binding were obtained from the literature, or estimated by fitting the model to the data. In the monkey model, the values for the rate of lysosomal degradation for antibodies (K), intraocular reflection coefficients (σ, σ σ), bidirectional rate of fluid circulation between the vitreous chamber and the aqueous chamber (Q), and permeability-surface area product of lens (PS) were estimated; and were found to be 31.5 h, 0.7629, 0.6982, 0.9999, 1.64 × 10 L/h, and 4.62 × 10 L/h, respectively. The monkey model could capture the data in plasma, aqueous humor, vitreous humor and retina reasonably well with the predictions being within twofold of the observed values. For the human model, only the value of K was estimated to fit the model to the plasma pharmacokinetics (PK) of mAbs and was found to be 24.4 h (4.14%). The human model could also capture the ocular PK data reasonably well with the predictions being within two- to threefold of observed values for the plasma, aqueous and vitreous humor. Thus, the proposed framework can be used to characterize and predict the PK of mAbs in the eye of monkey and human species following systemic and intravitreal administration. The model can also facilitate the development of new antibody-based therapeutics for the treatment of ocular diseases as well as predict ocular toxicities of such molecules following systemic administration.
我们之前发表了一个包含眼部隔室的 PBPK 模型，用于描述单克隆抗体（mAbs）在兔体内的处置情况。虽然兔在眼部研究中是常用的临床前物种，但非人类灵长类动物（NHPs）与人类的亲缘关系最密切，包括眼睛中的黄斑以及更高的序列同源性。然而，由于严格的伦理准则，它们在眼部研究中的应用受到限制。同样，在人类中，除了抽取房水（AH）外，不能采集眼部样本。因此，我们使用文献报道的数据将这个兔模型转化为猴和人类模型。描述组织体积、生理流动和 FcRn 结合的参数从文献中获得，或通过将模型拟合到数据来估计。在猴模型中，估算了抗体溶酶体降解速率（K）、眼内反射系数（σ、σ σ）、玻璃体液和房水之间双向流体循环速率（Q）以及晶状体的渗透表面积产物（PS）的值；结果分别为 31.5 h、0.7629、0.6982、0.9999、1.64 × 10 L/h 和 4.62 × 10 L/h。猴模型能够很好地捕捉到血浆、房水、玻璃体液和视网膜中的数据，预测值与观察值的比值在两倍以内。对于人类模型，仅估算 K 值以拟合模型至 mAbs 的血浆药代动力学（PK），结果为 24.4 h（4.14%）。人类模型也能够很好地捕捉到眼部 PK 数据，预测值与观察值的比值在两倍到三倍之间。因此，该框架可用于描述和预测单克隆抗体在猴和人类眼部的系统和玻璃体内给药后的 PK。该模型还可以促进新的基于抗体的治疗药物的开发，用于治疗眼部疾病，并预测此类分子在全身给药后的眼部毒性。
