Multi-scale Modeling of PK, Intracellular Signaling and Tumor Burden

A recent publication in the Journal of PK/PD presents a model-based analysis of the relative contributions of FLT3ITD and CDK4/6 inhibition on downstream signaling and tumor burden in acute myeloid leukemia.

FLT3 and CDK4/6 inhibitors: Signaling mechanisms and tumor burden in subcutaneous and orthotopic mouse models of acute myeloid leukemia

Yaping Zhang, Cheng-Pang Hsu, Jian-Feng Lu, Mita Kuchimanchi, Yu-Nien Sun, Ji Ma, Guifen Xu, Yilong Zhang, Yang Xu, Margaret Weidner, Justin Huard, David Z. D’Argenio, Journal of Pharmacokinetics and Pharmacodynamics. 41(6) :675-692, 2014 [PMC4226810]

FLT3ITD subtype acute myeloid leukemia (AML) has a poor prognosis with currently available therapies. A number of small molecule inhibitors of FLT3 and/or CDK4/6 are currently under development. A more complete and quantitative understanding of the mechanisms of actions of FLT3 and CDK4/6 inhibitors may better inform the development of current and future compounds that act on one or both of the molecular targets, and thus may lead to improved treatments for AML. In this study, we investigated in both subcutaneous and orthotopic AML mouse models, the mechanisms of action of three FLT3 and/or CDK4/6 inhibitors: AMG925 (Amgen), sorafenib (Bayer and Onyx), and quizartinib (AC220, Ambit Biosciences). A composite model was developed to integrate the plasma pharmacokinetics of these three compounds on their respective molecular targets, the coupling between the target pathways, as well as the resulting effects on tumor burden reduction in the subcutaneous xenograft model. A sequential modeling approach was used, wherein model structures and estimated parameters from upstream processes (e.g. PK, cellular signaling) were fixed for modeling subsequent downstream processes (cellular signaling, tumor burden). Pooled data analysis was employed for the plasma PK and cellular signaling modeling, while population modeling was applied to the subcutaneous and orthotopic tumor burden modeling. The resulting model allows the decomposition of the relative contributions of FLT3ITD and CDK4/6 inhibition on downstream signaling and tumor burden. In addition, the action of AMG925 on cellular signaling and tumor burden was further studied in an orthotopic tumor mouse model more closely representing the physiologically relevant environment for AML.

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