Tackle the Conundrums of Anti-Tumor Antibody Drug Development with PK/PD Modeling

Antibody based therapy is promising but encounters challenges in anti-tumor therapy. Delivery to tumor tissue is a major one. Insufficient delivery resulted in a heterogeneous intratumoral disposition due to binding site barrier effect. Preclinical studies have demonstrated this phenomenon in experiments. In contrast, there is no feasible technique to navigate this phenomenon in clinical settings. So, an assisting solution is to develop a quantitative tool to utilize comprehensive preclinical information to approximate how the phenomena affect clinical practice. This presentation will use cetuximab as a case study to introduce a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model to describe the heterogeneous intratumoral antibody distribution. The tumor associated kinetic events were collected from various preclinical studies then employed together with the clinical population PK data to estimate the heterogeneous intratumoral exposure in patients. Also, this work incorporated the uncertainties in preclinical experiments and variability in clinical settings. The simulation results revealed how the intratumoral exposure was inadequate. Therefore, this modeling methodology can be used to provide insightful understanding about antibody distribution in tumor tissues and shape the antibody drug development process from such critical issues as discrepancy between in vitro and in vivo, selection of targets, screening of candidates, evaluation of tumor target burden, selection of biomarker, and translation to clinical studies based on preclinical studies.