Preclinical Population PK/PD of TGF beta RI Kinase inhibitor for Cancer

Objectives: The primary objective of PK/PD modeling in preparation for the First Human Dose study was to estimate a pharmacologically effective dose range in humans based on preclinical data

Methods: Data from tumor growth kinetics Xenograft model in mice and from in vivo target inhibition (IVTI) in rats and in mice were incorporated in our PK/PD analysis.  The PK/PD model in mice integrated the time course of the pharmacokinetics of the compound, the inhibition of SMAD phosphorylation (biomarker) and tumor growth data in terms of pharmacodynamics.  An indirect response model was used to relate the predicted plasma concentrations with the observed pSMAD data. The model assumed the existence of factors within the tumor cell responsible for the synthesis and degradation of pSMAD.  A Gompertz model was applied to describe the tumor growth curve.  This model can be extended to further understand the relationship between the time course of the tumor growth and the time course of TGF-beta RI kinase inhibitor.  A PK/PD model in rats based on SMAD phosphorylation was also built in rats. This model incorporated the pharmacokinetics and the inhibition of the pSMAD from the IVTI studies.  This model supported an understanding of TGF-beta RI kinase inhibitor concentrations and the relationship to the inhibition of the SMAD phosphorylation.  Both models enabled prediction of the targeted inhibition of SMAD phosphorylation under different dosing regimens

Results and Conclusions: In both models, the variability of the biomarker was incorporated to assess the variability in the response, in order to simulate profiles in humans. Simulations were performed in order to assist the dose range selection for the First Human Dose (FHD) study.

Potentially, with these two approaches, the relationship between time course of TGF-beta RI kinase inhibitor concentrations and clinical tumor response was defined.  The PKPD modeling would provide guidance for the design of future studies, as these models will be updated as new data become available from the FHD study