Predicting human subcutaneous bioavailability of monoclonal antibodies using an open flow microperfusion porcine model.

Subcutaneous (SC) administration of monoclonal antibodies (mAbs) offers several advantages including patient self-administration, improved treatment adherence, and reduced healthcare costs. However, predicting human bioavailability remains challenging. This study presents a novel approach combining open flow microperfusion (OFM) technology in a porcine model with physiologically based pharmacokinetic (PBPK) modeling to investigate local mAb-tissue interactions and predict human bioavailability of three commercially available mAbs (alirocumab, brodalumab, secukinumab). mAb formulations were slowly infused via minimally invasive OFM probes into porcine SC tissue to minimize the formation of a SC injection site depot. Interstitial fluid (ISF) was sampled hourly with the same OFM probes. Tissue biopsies taken at standardized positions relative to the OFM probes were used to assess mAb concentrations in SC adipose tissue. These data provide a surrogate measure for mAb-tissue interactions such as mAb affinity to tissue binding and precipitation. Subsequently, rate constants describing diffusion and non-specific mAb binding to SC adipose tissue were estimated with a compartmental model for the SC environment taking into account the experimental design such as a washout sampling phase which removed loosely bound mAbs. OFM-derived parameters were integrated into the human PBPK model to simulate concentration-time profiles of the three mAbs in human systemic circulation. With predicted bioavailability values within ±5 % of human clinical data our approach significantly improved the prediction accuracy of human concentration-time profiles compared to standard models. Furthermore, tissue biopsies indicated an inverse correlation between local mAb retention and human SC bioavailability. Our integrated approach of OFM technology and OFM-informed PBPK modeling thus offers a robust strategy for predicting human SC bioavailability of mAbs.