Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, NY, 14214-8033, USA.
J Pharmacokinet Pharmacodyn. 2021 Oct;48(5):743-762. doi: 10.1007/s10928-021-09772-x. Epub 2021 Jun 19.
In the past, our lab proposed a two-pore PBPK model for different-size protein therapeutics using de novo derived parameters and the model was validated using plasma PK data of different-size antibody fragments digitized from the literature (Li Z, Shah DK, J Pharmacokinet Pharmacodynam 46(3):305-318, 2009). To further validate the model using tissue distribution data, whole-body biodistribution study of 6 different-size proteins in mice were conducted. Studied molecules covered a wide MW range (13-150 kDa). Plasma PK and tissue distribution profiles is 9 tissues were measured, including heart, lung, liver, spleen, kidney, skin, muscle, small intestine, large intestine. Tumor exposure of different-size proteins were also evaluated. The PBPK model was validated by comparing percentage predictive errors (%PE) between observed and model predicted results for each type of molecule in each tissue. Model validation showed that the two-pore PBPK model was able to predict plasma, tissues and tumor PK of all studied molecules relatively well. This model could serve as a platform for developing a generic PBPK model for protein therapeutics in the future.
过去，我们的实验室提出了一种双孔 PBPK 模型，用于不同大小的蛋白质治疗药物，使用从头推导的参数，并使用从文献中数字化的不同大小抗体片段的血浆 PK 数据验证该模型（Li Z，Shah DK，J Pharmacokinet Pharmacodynam 46（3）：305-318，2009）。为了使用组织分布数据进一步验证模型，我们在小鼠中进行了 6 种不同大小的蛋白质的全身生物分布研究。研究的分子涵盖了广泛的 MW 范围（13-150 kDa）。测量了 9 种组织中的血浆 PK 和组织分布谱，包括心脏、肺、肝、脾、肾、皮肤、肌肉、小肠、大肠。还评估了不同大小蛋白质的肿瘤暴露情况。通过比较每种组织中每种分子的观察结果和模型预测结果的百分比预测误差（%PE），验证了 PBPK 模型。模型验证表明，双孔 PBPK 模型能够相对较好地预测所有研究分子的血浆、组织和肿瘤 PK。该模型可以作为未来开发蛋白质治疗药物通用 PBPK 模型的平台。
