Two-pore physiologically based pharmacokinetic model validation using whole-body biodistribution of trastuzumab and different-size fragments in mice

• DOI: 10.1007/s10928-021-09772-x
• Publication Date: 2021-06-19T06:02:41Z
• Authors: Zhe Li; Yingyi Li; Hsuan Ping Chang; Xiaoying Yu; Dhaval K. Shah
• Keywords: Mice; 0303 health sciences; 03 medical and health sciences; Cell Line, Tumor; Neoplasms; Animals; Antibodies, Monoclonal; Humans; Mice, Nude; Tissue Distribution; Trastuzumab; Models, Biological

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.