Abstract B154: Application of preclinical combination pharmacokinetic(PK)/efficacy(E) modeling to investigate and translate the preclinical scheduling effect for MLN1117 and Taxotere combination
Authors: Kadakia Ekta , Iartchouk Natasha , Kannan Karuppiah , Song Keli , Mei Zhang Dong , Zopf Christopher , Zopf Christopher , Patel Munjal , Patel Chirag , Chowdhury Swapan , Shyu Wen Chyi , Wu Jing-Tao , Chakravarty Arijit 
Published: May 2016

Abstract
During preclinical development of investigational compound, MLN1117, combination efficacy studies of MLN1117 and Taxotere in mice bearing lung cancer tumor xenografts indicated the presence of a scheduling effect. In many instances, pre-dosing Taxotere resulted in improved tumor growth inhibition as compared to concomitant dosing with MLN1117. Furthermore both in vitro and in vivo PD studies demonstrated that sequential administration of MLN1117 (PI3Ka inhibitor) and Taxotere resulted in increased apoptosis as compared to concomitant treatment.
To further investigate and translate these observations, combination PK/E modeling was performed on preclinical PK and efficacy data. A scheduling efficacy study was executed in small cell lung cancer NCI-H1048 model. The study was designed to compare the anti-tumor activity of the combination under varying levels of PK concomitance between the two compounds. Using a non-linear mixed effects approach, dynamic PK/E modeling was performed to describe the individual mouse tumor growth curves as a function of the instantaneous plasma drug concentration of MLN1117 and Taxotere. The combination effect in the dynamic model was described using the following expression:
(PK/E)MLN1117 + (PK/E)Taxotere + Tau* (PK/E)Taxotere * (PK/E)MLN1117
The combination interaction (Tau) between MLN1117 and Taxotere was estimated to be negative but associated with significant inter-tumor variability. A negative Tau implied the combination behaved sub-additively under conditions of concomitant dosing. Pre-dosing Taxotere made the combination non-concomitant which explains the improved anti-tumor activity associated with it. The variability associated with the positive effects of pre-dosing Taxotere or non-concomitant dosing was attributed to the variability in Tau. In general, the modeling results favored the use of non-concomitant dosing for the MLN1117/Taxotere combination to eliminate the dependence of the combination efficacy on the negative Tau.
Although the emphasis of this study has been on SCLC cancer model NCI-H1048, early preclinical data from other cancer models of different origin indicate that this phenomenon could be ubiquitous. The combination PK/E model though empirical in nature, provided a useful and translatable tool to guide combination schedule selection. The modeling framework focused on understanding the behavior of the combination i.e. combination interaction term (Tau) and translating this understanding to optimize combination scheduling choices for the clinic.
Citation Format: Ekta Kadakia, Natasha Iartchouk, Karuppiah Kannan, Keli Song, Dong Mei Zhang, Christopher Zopf, Christopher Zopf, Munjal Patel, Chirag Patel, Swapan Chowdhury, Wen Chyi Shyu, Jing-Tao Wu, Arijit Chakravarty. Application of preclinical combination pharmacokinetic(PK)/efficacy(E) modeling to investigate and translate the preclinical scheduling effect for MLN1117 and Taxotere combination. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B154.