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 <i>in vitro</i> 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 <i>in vitro</i> 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 (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>A</mml:mi><mml:mi>U</mml:mi><mml:mrow><mml:msub><mml:mi>C</mml:mi><mml:mrow><mml:mfenced><mml:mrow><mml:mn>0</mml:mn><mml:mo>-</mml:mo><mml:mn>672</mml:mn><mml:mi>h</mml:mi></mml:mrow></mml:mfenced></mml:mrow></mml:msub></mml:mrow></mml:math>: 1.74 × 10⁶ -1.38 × 10⁷ 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 <i>F</i>1 and <i>F</i>2 modulating pinocytosis rate and convective transport, respectively, were estimated for each mAb with mostly good precision (coefficient of variation (CV%) <30%). <i>F</i>1 was estimated to be the mean and standard deviation of 0.961 ± 0.593, and <i>F</i>2 was estimated to be 2.13 ± 2.62. Using principal component analysis to correlate the regressed values of <i>F</i>1/<i>F</i>2 versus the multidimensional dataset composed of our panel of <i>in vitro</i> assays, we found that heparin chromatography retention time emerged as the predictive covariate to the mAb-specific <i>F</i>1, whereas <i>F</i>2 variability cannot be well explained by these assays. A sigmoidal relationship between <i>F</i>1 and the identified covariate was incorporated within the PBPK framework. A sensitivity analysis suggested plasma concentrations to be most sensitive to <i>F</i>1 when <i>F</i>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 <i>a priori</i> identification of mAb candidates with unfavorable PK.