Abstract 2668: Applying mechanistic PK/PD modeling to describe the efficacy of AZD8835 (PI3Kalpha/delta inhibitor) in a mouse xenograft breast tumor model at different dosing schedules
Authors: Morentin Gutierrez Pablo , Hudson Kevin , Hancox Urs J. , Ward Lara T. , Polanska Urszula M. , Cumberbatch Marie , Cruzalegui Francisco H. 
Published: August 2015

Introduction: PI3Kα inhibitors have shown antitumor efficacy in PIK3CA-mutant xenograft models when continued inhibition of the pathway is maintained (Fritsch et al., Mol Cancer Ther 2014; 13:1117-1129). The level of efficacy can be linked to the amount and duration of pathway inhibition using a proximal biomarker (pAKT). AZD8835 (a selective PI3Kα/δ inhibitor) delivers antitumor efficacy in a mouse xenografted breast cancer cell line (BT474c) using either a continuous or intermittent dosing schedule. However, the efficacy observed with the intermittent dosing schedule cannot be predicted based on the changes in the proximal biomarker alone. We present a novel mathematical model that links the efficacy observed with both schedules to the drug concentrations in plasma via drug-induced changes in the proximal biomarker (pAKT) as well as in a marker of apoptosis (Cleaved Caspase 3, CC3).

Methods: All in vivo work was carried out in the mouse BT474c xenograft model. A mathematical pharmacokinetic/pharmacodynamic (PK/PD) model was built to link plasma concentrations of AZD8835 to both the proximal biomarker of pathway inhibition pAKT (measured using Western blot) and a distal marker of apoptosis, CC3 (measured by IHC). The output (CC3 and pAKT) of this model was used to drive an adaptation of a well-known model for tumor growth inhibition (Simeoni et al. Cancer Res 2004; 64:1094-1101). All doses and schedules were fitted simultaneously in a population approach.

Results: The PK/PD model described well the time course of both biomarkers (pAKT and CC3), for a range of both continuous and intermittent doses. The CC3 PK/PD model captured the observation that on continuous dosing the CC3 signal diminishes while the signal can be maintained with intermittent dosing. By incorporating the time course of change in pAKT and CC3, the proposed model was able to simultaneously describe the effects of the different AZD8835 doses and schedules (continuous and intermittent) on tumor volume.

Conclusions: Incorporating more mechanistic features to the drug-induced tumor growth inhibition model provides valuable insight to elucidate the relative balance of the anti-proliferative and pro-apoptotic consequences of PI3Kα/δ inhibition in a xenografted breast cancer cell line. This balance is dependent not only on the dose but also on the schedule. The model supports exploration of intermittent dosing in the clinic to help manage the chronic toxicology associated with PI3K pathway inhibition.

Citation Format: Pablo Morentin Gutierrez, Kevin Hudson, Urs J. Hancox, Lara T. Ward, Urszula M. Polanska, Marie Cumberbatch, Francisco H. Cruzalegui. Applying mechanistic PK/PD modeling to describe the efficacy of AZD8835 (PI3Kalpha/delta inhibitor) in a mouse xenograft breast tumor model at different dosing schedules. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2668. doi:10.1158/1538-7445.AM2015-2668