With the increasing prevalence of subcutaneous administration of peptides, understanding their release and absorption is key to designing formulations with desired pharmacokinetics. Though the absorption of monoclonal antibodies (mAbs) has been widely explored through computational modeling, that of peptides remains poorly understood, as key features of peptide absorption, including concentration-dependent oligomerization and reversible binding with serum albumin and extracellular matrix, have not been captured. In this work, we present a first-of-its-kind approach to simulating subcutaneous administration of peptides that couples a high-fidelity tissue-level poroelastic model with a systemic compartment pharmacokinetic model. While accounting for competing binding and oligomerization tendencies of peptides, the model not only captures the process of injection but also tracks the absorption over subsequent days. We demonstrate the model using a single-dose administration of semaglutide and validate it against experimentally observed pharmacokinetic parameters. The results show the distribution of the different forms of the injected peptide throughout the body and describe the role of binding in sustaining its release. The model also reveals novel mechanisms, such as albumin-bound monomers enveloping the plume and the balance of oligomerization and binding in early stages of peptide absorption.
Kuhar, S., Li, C., Ardekani, A. M.
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