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

Cancer Chemother Pharmacol. 2013 May;71(5):1147-57. doi: 10.1007/s00280-013-2107-z. Epub 2013 Feb 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / pharmacokinetics
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Bevacizumab
  • Cell Line, Tumor
  • HT29 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Biological*
  • Neoplasms / blood supply
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Nonlinear Dynamics
  • Regression Analysis
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Bevacizumab