Yue Gao1, Yan Li1, Simon Zhou1*, Ho-pi Lin2, Angela James1, Maria Palmisano1, Rama K Narla3 and Sophie X Peng3
1Celgene Cooperation, Summit, NJ, USA; 2Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 3Celgene Cooperation, San Diego, CA, USA
Objectives: In this study, the PK and PD data of a potent and selective mTOR kinase inhibitor were collected in xenografted tumor models in mice. A PK/PD model was developed to link drug exposures with inhibition of tumor growth to explore xenograft experiment designs and improve efficiency.
Material and Methods: PK data and tumor volume data collected from xenograft mice model under 7 different doses/regimens were used to develop PK/PD models. The indirect PD model was constructed to mimic physiologic processes of tumor growth and drug effect on the inhibition of tumor growth rate. In the PK portion of the model, there were a total of 5 fixed effect parameters and in the PD portion of the model, there were a total of 3 fixed effect parameters. Simulations were conducted to explore the minimal number of doses/regimen and optimal experiment designs to effectively capture drug effect.
Results: A 2-compartment PK model well-characterized the PK profiles of the mTOR inhibitor. The distribution of the mTOR kinase inhibitor is altered and distinct in xenograft mice as compared to healthy mice. In spite of this difference, PK from healthy mice adequately predict the tumor shrinkage in xenograft mice.
An indirect PK/PD model adequately captured the features of tumor growth and the anticancer effect of the mTOR kinase inhibitor, which provided reliable parameter estimates. Analyses shown that the net tumor growth rate defined as kgrowth-kdeath and drug effect of IC50 are the key drivers of the tumor shrinkage.
For the mTOR kinase inhibitor studied, multiple simulations and subsequent PK/PD analyses demonstrated that four treatment groups of QD doses plus a placebo treatment group could adequately characterize the tumor shrinkage and the resulted model could be used to predict alternative dose levels and dose regimens with good accuracy, additional doses/regimens provided redundant information.
conclusions: In our study with the mTOR kinase inhibitor, the PK exposure from the healthy mice was adequate to tumor shrinkage in xenograft mice. The indirect PK/PD link model well-captured the key drivers of the drug effect and adequately described the tumor shrinkage. The PK/PD modeling and simulation optimized the design and improved efficiency of the xenograft experiments.
Reference: PAGE 23 (2014) Abstr 3233 [www.page-meeting.org/?abstract=3233]
Poster: Drug/Disease modeling - Other topics