Translational physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies.

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Sanika Naware, David Bussing, Dhaval K Shah
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引用次数: 0

Abstract

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 (Kdeg), intraocular reflection coefficients (σaq, σret, σcho), bidirectional rate of fluid circulation between the vitreous chamber and the aqueous chamber (QVA), and permeability-surface area product of lens (PSlens) were estimated; and were found to be 31.5 h-1, 0.7629, 0.6982, 0.9999, 1.64 × 10-5 L/h, and 4.62 × 10-7 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 Kdeg was estimated to fit the model to the plasma pharmacokinetics (PK) of mAbs and was found to be 24.4 h-1 (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.

Abstract Image

基于生理学的单克隆抗体眼部处置药代动力学转化模型。
我们以前发表过一个包括眼部区室的 PBPK 模型,用于描述单克隆抗体(mAbs)在兔子体内的处置。兔子是眼科研究中常用的临床前物种,而非人灵长类动物(NHPs)在系统发育上与人类最为相似,包括眼睛中存在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,人类的眼部样本也不能采集,只能采集房水(AH)。因此,我们利用文献报道的数据集将这一兔子模型转化为猴子和人类物种。描述组织体积、生理流量和 FcRn 结合的参数均从文献中获得,或通过模型与数据的拟合进行估算。在猴子模型中,对抗体溶酶体降解率(Kdeg)、眼内反射系数(σaq、σret、σccho)、玻璃体腔和水腔之间液体循环的双向速率(QVA)以及晶状体的渗透性-表面积乘积(PSlens)进行了估算,结果发现这些数值分别为 31.5 h-1、0.7629、0.6982、0.9999、1.64 × 10-5 L/h 和 4.62 × 10-7 L/h。猴子模型能很好地捕捉血浆、水样物质、玻璃体和视网膜中的数据,预测值与观测值相差不到两倍。对于人的模型,只对 Kdeg 值进行了估计,使模型符合 mAbs 的血浆药代动力学(PK),结果发现 Kdeg 值为 24.4 h-1 (4.14%)。人体模型也能很好地捕捉眼部 PK 数据,对血浆、水和玻璃体的预测值均在观察值的 2 到 3 倍范围内。因此,所提出的框架可用于描述和预测全身给药和玻璃体内给药后 mAbs 在猴眼和人眼中的 PK。该模型还有助于开发治疗眼部疾病的新型抗体疗法,以及预测此类分子在全身给药后的眼部毒性。
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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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