Utility of physiologically based pharmacokinetic modeling to predict inter-antibody variability in monoclonal antibody pharmacokinetics in mice.

In this investigation, we tested the hypothesis that a physiologically based pharmacokinetic (PBPK) model incorporating measured metrics of off-target binding can largely explain the inter-antibody variability in monoclonal antibody (mAb) pharmacokinetics (PK). A diverse panel of 83 mAbs was evaluated for PK in wild-type mice and subjected to 10 assays to measure major physiochemical attributes. After excluding for target-mediated elimination and immunogenicity, 56 of the remaining mAbs with an eight-fold variability in the area under the curve (: 1.74 × 10 -1.38 × 10 ng∙h/mL) and 10-fold difference in clearance (2.55-26.4 mL/day/kg) formed the training set for this investigation. Using a PBPK framework, mAb-dependent coefficients 1 and 2 modulating pinocytosis rate and convective transport, respectively, were estimated for each mAb with mostly good precision (coefficient of variation (CV%) <30%). 1 was estimated to be the mean and standard deviation of 0.961 ± 0.593, and 2 was estimated to be 2.13 ± 2.62. Using principal component analysis to correlate the regressed values of 1/2 versus the multidimensional dataset composed of our panel of assays, we found that heparin chromatography retention time emerged as the predictive covariate to the mAb-specific 1, whereas 2 variability cannot be well explained by these assays. A sigmoidal relationship between 1 and the identified covariate was incorporated within the PBPK framework. A sensitivity analysis suggested plasma concentrations to be most sensitive to 1 when 1 > 1. The predictive utility of the developed PBPK model was evaluated against a separate panel of 14 mAbs biased toward high clearance, among which area under the curve of PK data of 12 mAbs was predicted within 2.5-fold error, and the positive and negative predictive values for clearance prediction were 85% and 100%, respectively. MAb heparin chromatography assay output allowed identification of mAb candidates with unfavorable PK.