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A Two-Pore Physiologically Based Pharmacokinetic Model to Predict Subcutaneously Administered Different-Size Antibody/Antibody Fragments

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Abstract

Quantitative modeling of the subcutaneous absorption processes of protein therapeutics is challenging. Here we have proposed a “two-pore” PBPK model that is able to simultaneously characterize plasma PK of different-size protein therapeutics in mice. The skin compartment is evolved to mechanistically account for the absorption pathways through lymph and blood capillaries, as well as local degradation at the SC injection site. The model is developed using in-house plasma PK data generated following subcutaneous administration of 6 different-size protein therapeutics (13–150 kDa) in mice. The model was able to capture plasma PK of all molecules following intravenous and subcutaneous administration relatively well. From the observed plasma PK profiles, as well as from the model simulation result, several important PK descriptors were found to be dependent on protein size for FcRn nonbinding molecules. A positive correlation was found between Tmax and protein size. A “U” shape relationship was found between Cmax and protein size. Negative correlations were observed between bioavailability (F) and local degradation rate (kdeg,SC), and F and protein size. Pathway analysis of the model was conducted for the subcutaneous absorption process, and continuous relationships were established between the percentage of absorption through lymphatic and vascular pathways and protein size. This PBPK model could serve as a platform for the development of different-size protein therapeutics and will be scaled up to humans for translational studies in the future.

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Acknowledgements

This work was supported by the 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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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, New York, 14214, USA

    Zhe Li, Xiaoying Yu, Yingyi Li, Ashwni Verma, Hsuan Ping Chang & Dhaval K. Shah

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  1. Zhe Li
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  2. Xiaoying Yu
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  3. Yingyi Li
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  4. Ashwni Verma
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  6. Dhaval K. Shah
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Correspondence to Dhaval K. Shah.

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Li, Z., Yu, X., Li, Y. et al. A Two-Pore Physiologically Based Pharmacokinetic Model to Predict Subcutaneously Administered Different-Size Antibody/Antibody Fragments. AAPS J 23, 62 (2021). https://doi.org/10.1208/s12248-021-00588-8

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