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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]

Background and Purpose: Savolitinib (AZD6094, HMPL‐504, volitinib) is an oral, potent, and highly MET receptor TK inhibitor. This series of studies aimed to develop a pharmacokinetic–pharmacodynamic (PK/PD) model to link inhibition of MET phosphorylation (pMET) by savolitinib with anti‐tumour activity. Experimental Approach Cell line‐derived xenograft (CDX) experiments using human lung cancer (EBC‐1) and gastric cancer (MKN‐45) cells were conducted in athymic nude mice using a variety of doses and schedules of savolitinib. Tumour pMET changes and growth inhibition were calculated after 28 days. Population PK/PD techniques were used to construct a PK/PD model for savolitinib. Key Results: Savolitinib showed dose‐ and dose frequency‐dependent anti‐tumour activity in the CDX models, with more frequent, lower dosing schedules (e.g., twice daily) being more effective than intermittent, higher dosing schedules (e.g., 4 days on/3 days off or 2 days on/5 days off). There was a clear exposure–response relationship, with maximal suppression of pMET of >90%. Data from additional CDX and patient‐derived xenograft (PDX) models overlapped, allowing calculation of a single EC50 of 0.38 ng·ml−1. Tumour growth modelling demonstrated that prolonged, high levels of pMET inhibition (>90%) were required for tumour stasis and regression in the models. Conclusion and Implications: High and persistent levels of MET inhibition by savolitinib were needed for optimal monotherapy anti‐tumour activity in preclinical models. The modelling framework developed here can be used to translate tumour growth inhibition from the mouse to human and thus guide choice of clinical dose and schedule. [ABSTRACT FROM AUTHOR]

Quantitative systems pharmacology (QSP) approaches have been increasingly applied in the pharmaceutical since the landmark white paper published in 2011 by a National Institutes of Health working group brought attention to the discipline. In this perspective, we discuss QSP in the context of other modeling approaches and highlight the impact of QSP across various stages of drug development and therapeutic areas. We discuss challenges to the field as well as future opportunities. [ABSTRACT FROM AUTHOR]