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


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.

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This work was supported by National Institute of General Medical Sciences grant [GM114179]. D.K.S. is also supported by and National Institute of Allergy and Infectious Diseases Grant [AI138195] and National Cancer Institute Grant [R01CA246785].

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Correspondence to Dhaval K. Shah.

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Li, Z., Li, Y., Chang, H.P. et al. Two-pore physiologically based pharmacokinetic model validation using whole-body biodistribution of trastuzumab and different-size fragments in mice. J Pharmacokinet Pharmacodyn 48, 743–762 (2021).

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  • Monoclonal antibody (mAb)
  • Antibody fragments
  • Physiologically based pharmacokinetic (PBPK) model
  • Two-pore theory