基于生理的两孔药代动力学(PBPK)模型已证明其在描述不同大小蛋白质的药代动力学(PK)方面的潜力。然而,所有现有的双孔模型都缺乏用于验证或种间外推的不同蛋白质。为了填补空白,在这里,我们已经开发和优化了一个翻译的两孔PBPK模型,可以表征不同大小的蛋白质在小鼠的血浆和组织分布,老鼠,猴子,和人类。用于模型开发的数据集包括超过15种类型的蛋白质:IgG(150kDa),F(ab)2(100kDa),微型车身(80kDa),含Fc蛋白(205、200、110、105、92、84、81、65或60kDa),白蛋白缀合物(85.7kDa),白蛋白(67kDa),Fab(50kDa),双抗体(50kDa),scFv(27kDa),dAb2(23.5kDa),具有白蛋白结合域(26、23.5、22、16、14或13kDa)的蛋白质,纳米抗体(13kDa),和其他蛋白质(110、65或60kDa)。PBPK模型包含:(i)通过扩散和过滤通过大小孔的分子量(MW)依赖性外渗,(ii)MW依赖性肾滤过,(iii)内体FcRn介导的保护免受IgG和白蛋白相关形式的分解代谢,和(iv)竞争来自内源性IgG和白蛋白的FcRn结合。最终的模型可以很好地表征大多数这些蛋白质的PK,曲线下的面积预测在两倍的误差内。该模型还提供了对肾脏过滤和溶酶体降解对蛋白质完全消除的贡献的见解,以及细胞旁对流/扩散和胞吞对外渗的贡献。这里介绍的PBPK模型代表了一种交叉模式,可用于开发新生物制品的跨物种平台。
Two-pore physiologically based pharmacokinetic (PBPK) modeling has demonstrated its potential in describing the pharmacokinetics (PK) of different-size proteins. However, all existing two-pore models lack either diverse proteins for validation or interspecies extrapolation. To fill the gap, here we have developed and optimized a translational two-pore PBPK model that can characterize plasma and tissue disposition of different-size proteins in mice, rats, monkeys, and humans. Datasets used for model development include more than 15 types of proteins: IgG (150 kDa), F(ab)2 (100 kDa), minibody (80 kDa), Fc-containing proteins (205, 200, 110, 105, 92, 84, 81, 65, or 60 kDa), albumin conjugate (85.7 kDa), albumin (67 kDa), Fab (50 kDa), diabody (50 kDa), scFv (27 kDa), dAb2 (23.5 kDa), proteins with an albumin-binding domain (26, 23.5, 22, 16, 14, or 13 kDa), nanobody (13 kDa), and other proteins (110, 65, or 60 kDa). The PBPK model incorporates: (i) molecular weight (MW)-dependent extravasation through large and small pores via diffusion and filtration, (ii) MW-dependent renal filtration, (iii) endosomal FcRn-mediated protection from catabolism for IgG and albumin-related modalities, and (iv) competition for FcRn binding from endogenous IgG and albumin. The finalized model can well characterize PK of most of these proteins, with area under the curve predicted within two-fold error. The model also provides insights into contribution of renal filtration and lysosomal degradation towards total elimination of proteins, and contribution of paracellular convection/diffusion and transcytosis towards extravasation. The PBPK model presented here represents a cross-modality, cross-species platform that can be used for development of novel biologics.