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Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth after administration of an anti-angiogenic agent, bevacizumab, as single-agent and combination therapy in tumor xenografts.

Abstract：

PURPOSE:Pharmacokinetic-pharmacodynamic (PK-PD) models able to predict the action of anticancer compounds in tumor xenografts have an important impact on drug development. In case of anti-angiogenic compounds, many of the available models show difficulties in their applications, as they are based on a cell kill hypothesis, while these drugs act on the tumor vascularization, without a direct tumor cell kill effect. For this reason, a PK-PD model able to describe the tumor growth modulation following treatment with a cytostatic therapy, as opposed to a cytotoxic treatment, is proposed here. METHODS:Untreated tumor growth was described using an exponential growth phase followed by a linear one. The effect of anti-angiogenic compounds was implemented using an inhibitory effect on the growth function. The model was tested on a number of experiments in tumor-bearing mice given the anti-angiogenic drug bevacizumab either alone or in combination with another investigational compound. Nonlinear regression techniques were used for estimating the model parameters. RESULTS:The model successfully captured the tumor growth data following different bevacizumab dosing regimens, allowing to estimate experiment-independent parameters. A combination model was also developed under a 'no-interaction' assumption to assess the effect of the combination of bevacizumab with a target-oriented agent. The observation of a significant difference between model-predicted and observed tumor growth curves was suggestive of the presence of a pharmacological interaction that was further accommodated into the model. CONCLUSIONS:This approach can be used for optimizing the design of preclinical experiments. With all the inherent limitations, the estimated experiment-independent model parameters can be used to provide useful indications for the single-agent and combination regimens to be explored in the subsequent development phases.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Rocchetti M,Germani M,Del Bene F,Poggesi I,Magni P,Pesenti E,De Nicolao G

doi

10.1007/s00280-013-2107-z

subject

Has Abstract

pub_date

2013-05-01 00:00:00

pages

1147-57

issue

eissn

0344-5704

issn

1432-0843

journal_volume

pub_type

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Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth after administration of an anti-angiogenic agent, bevacizumab, as single-agent and combination therapy in tumor xenografts.