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In vivo models have been crucial for developing our understanding of key processes associated with human disease and developing novel therapeutics. These in vivo studies are becoming increasingly complex, requiring long-term efficacy data and additional supportive datasets such as pharmacokinetic profiles and analysis of multiple biomarkers of pharmacodynamic response and efficacy. Moreover, a new agent will be investigated in many different models and often in combination with other drugs. Despite advances across the industry integrating and analysing complex datasets, management of in vivo data remains an ongoing challenge across the industry. Here, we describe a project that has successfully delivered a working solution to integrate pharmacokinetic, biomarker and efficacy data, independent of therapy area. [ABSTRACT FROM AUTHOR]

Trastuzumab deruxtecan (T‐DXd; DS‐8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)‐directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T‐DXd was administered in tumor‐bearing mice carrying NCI‐N87, Capan‐1, JIMT‐1, and MDA‐MB‐468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T‐DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response. A positive relationship was observed between released DXd concentrations in tumor and HER2 expression, with NCI‐N87 xenografts characterized by the highest exposures compared to the remaining cell lines. γΗ2AX and pRAD50 demonstrated a sustained increase over several days occurring with a time delay relative to tumoral‐released DXd concentrations. In vitro investigations of cell‐based DXd disposition facilitated the characterization of DXd kinetics across tumor cells. These outputs were incorporated into a mechanistic mathematical model, utilized to describe PK/PD trends. The model captured plasma PK across dosing arms as well as tumor PK in NCI‐N87, Capan‐1, and MDA‐MB‐468 models; tumor concentrations in JIMT‐1 xenografts required additional parameter adjustments reflective of complex receptor dynamics. γΗ2AX longitudinal trends were well characterized via a unified PD model implemented across xenografts demonstrating the robustness of measured PD trends. This work supports the application of a mechanistic model as a quantitative tool, reliably projecting tumor payload concentrations upon T‐DXd administration, as the first step towards preclinical‐to‐clinical translation. [ABSTRACT FROM AUTHOR]