Parallel-Competitive Absorption-Presystemic Metabolism Model for Subcutaneous Bioavailability Prediction of...

Monoclonal antibody therapeutics are often administered subcutaneously rather than intravenously to improve patient compliance and reduce healthcare costs. However, systemic absorption after a subcutaneous injection is often incomplete and variable. The bioavailability prediction model applied herein utilized a two-compartment pharmacokinetic framework in conjunction with parallel-competitive absorption and presystemic metabolism pathways. This study aimed to broaden the former validation of human bioavailability prediction by including linear and nonlinear-pharmacokinetics compounds. Validation was significantly expanded using a data set from 79 monoclonal antibodies (mAbs), spanning a bioavailability range of 29-100% (and a geometric mean bioavailability of 66%). By applying a single absorption rate constant alongside compound-specific estimates of presystemic metabolism rates, proportional to systemic clearance parameters, human subcutaneous bioavailability predictions were generated with a root-mean-square error (RMSE) of 13.1%. This mechanistic predictive method offers a preliminary estimate of subcutaneous bioavailability solely on the basis of pharmacokinetic data, which can be derived from intravenous administration.