Tumor growth and angiogenesis inhibition modeling: Effects of pazopanib on preclinical and clinical tumor size data
Aziz Ouerdani (1), Herbert Struemper (2), Ben Suttle (2), Daniele Ouellet (2) and Benjamin Ribba (1)
(1) Inria Sophia-Antipolis Méditerranée, France, (2) Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, RTP, NC, USA
Objectives: To develop a mixed-effects model to describe the dynamic of tumor volume of renal cell carcinoma (RCC) xenograft in mice treated by pazopanib, an antiangiogenic compound. The model is used to leverage available tumor size data from a pazopanib phase II study and to propose new hypotheses on the mechanisms of action of the drug in patients.
Methods: 32 mice with human RCC xenografts were administered pazopanib  orally once daily for 24 days and tumor volume was measured twice a week (n=8 observations/mice). Longitudinal tumor size data from 47 patients with metastatic RCC treated by an oral daily dose of 800mg of pazopanib were analyzed . Data were analyzed using Monolix and Nonmem. Model selection was based on the goodness of fit plots, objective function value (OFV) and BIC.
Results: The tumor growth and angiogenesis model consists of a system of nonlinear ordinary differential equations. Tumor volume (V) was described by a logistic growth dependent on carrying capacity (K) accounting for tumor angiogenesis . Drug action was modeled by reducing (1) K or (2) V or (3) both (simultaneous effects on K and V). The latter model gave the best results for the pre-clinical data (ΔOFV was -67 and -47 compared to individual effect on K and V, respectively) suggesting pazopanib demonstrates both cytotoxic and antiangiogenic effects. This model, with dual mechanisms of action also was able to fit the clinical tumor size data best (BIC decrease was -77 and -38, respectively). Tumor regrowth after initial shrinkage due to the short-lived cytotoxic effect (effect on V) and subsequent decay due to the longer-lasting antiangiogenic effect (effect on K) were observed in mice after 4 and 19 days of treatment. 13% of patients have profiles consistent with the pattern of initial tumor size decrease followed by intermittent increase followed by long-term decrease. In 4 of 5 patients that dropped-out due to PD, model simulation predicts tumor shrinkage after initial growth.
Conclusions: Our model suggests that pazopanib exerts both cytotoxic and antiangiogenic effects in mice which may also occur in humans. The potential for a second decline in tumor size in a subset of patients, suggests that with this combination of mechanisms, PD may be identified prematurely in some subjects and longer treatment/follow-up may be beneficial.
The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115156, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The DDMoRe project is also supported by financial contribution from Academic and SME partners. This work does not necessarily represent the view of all DDMoRe partners.
 Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther (2007) 6: 2012-21.
 Hutson TE, Davis ID, Machiels JP, et al. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol 2010 28: 475-80.
 Wilson S, Modeling the synergism between the anti-angiogenic drug sunitinib and irinotecan in xenografted mice. PAGE 22 (2013) Abstr 2826 [www.page-meeting.org/?abstract=2826]