2011 - Athens - Greece

PAGE 2011: Oncology
James Yates

Characterisation of Xenograft Response to Docetaxel by Nonlinear Mixed Effects Modelling

James WT Yates

AstraZeneca, Alderley Edge, SK10 4TG

Objectives: The human derived Xenograft tumour model is one of the main pre-clinical disease models used in oncology drug R&D. In the xenograftted PC3 cell-line a steep and variable dose response to Docetaxel (Taxotere«) has been observed. This can make the design of combination therapy experiments challenging. The aim therefore was to develop a "Population" model of the Pharmacokinetics and Tumour growth inhibition of Taxotere that can be used to simulate the response to untested doses.

Methods: All analysis was performed in NONMEM v6 and R v2.9. A two compartment model was fitted to Pharmacokinetic data from mice. Xenograffted tumour growth data was also available from two separate studies where doses of 15 and 20mg/kg were tested. There were no pharmacokinetic data from these studies; therefore PK was simulated for these studies using the mean parameter values. A second mixed effects model was developed using the Simeoni model to describe the tumour growth curves.
The identified model was used simulate the response to untested doses. The simulations were then summarised in terms of mean and standard deviation of tumour growth inhibition for each dose across the studies as well as the proportion of studies for which a particular dose had a significant effect against control.

Results: The simulated dose response suggested that it would be difficult to recommend a dose that would give a moderate response (~50% growth inhibition) whilst being significant against control. However a dose of 5mg/kg gave a mean response of 51.4 percent growth inhibition with an 80% chance of being significant against control.
As a form of model validation, data resulting from a previously untested dose 7.5mg/kg) was compared to a monte carlo simulation of the model at that dose. There were some disparities noted. However the response was in the range suggested by the simulations

Conclusions: Using a mixed effects model approach the xenograft response to a chemotherapeutic was characterised. It is clear from the model validation that inter-study variability should be characterised as well.

[1] Simeoni et al. 2004. Predictive Pharmacokinetic-Pharmacodynamic Modeling of Tumour Growth Kinetics in Xenograft Models after Administration of Anticancer Agents.

Reference: PAGE 20 (2011) Abstr 2076 [www.page-meeting.org/?abstract=2076]
Poster: Oncology