A predictive pharmacokinetic-pharmacodynamic model of tumor growth kinetics in xenograft mice after administration of anticancer agents given in combination

Cancer Chemother Pharmacol. 2013 Aug;72(2):471-82. doi: 10.1007/s00280-013-2208-8. Epub 2013 Jun 29.

Abstract

Purpose: In clinical oncology, combination treatments are widely used and increasingly preferred over single drug administrations. A better characterization of the interaction between drug effects and the selection of synergistic combinations represent an open challenge in drug development process. To this aim, preclinical studies are routinely performed, even if they are only qualitatively analyzed due to the lack of generally applicable mathematical models.

Methods: This paper presents a new pharmacokinetic-pharmacodynamic model that, starting from the well-known single agent Simeoni TGI model, is able to describe tumor growth in xenograft mice after the co-administration of two anticancer agents. Due to the drug action, tumor cells are divided in two groups: damaged and not damaged ones. The damaging rate has two terms proportional to drug concentrations (as in the single drug administration model) and one interaction term proportional to their product. Six of the eight pharmacodynamic parameters assume the same value as in the corresponding single drug models. Only one parameter summarizes the interaction, and it can be used to compute two important indexes that are a clear way to score the synergistic/antagonistic interaction among drug effects.

Results: The model was successfully applied to four new compounds co-administered with four drugs already available on the market for the treatment of three different tumor cell lines. It also provided reliable predictions of different combination regimens in which the same drugs were administered at different doses/schedules.

Conclusions: A good and quantitative measurement of the intensity and nature of interaction between drug effects, as well as the capability to correctly predict new combination arms, suggest the use of this generally applicable model for supporting the experiment optimal design and the prioritization of different therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Area Under Curve
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Cell Line, Tumor
  • Cisplatin / administration & dosage
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Fluorouracil / administration & dosage
  • Humans
  • Irinotecan
  • Kinetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Biological*
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology*
  • Xenograft Model Antitumor Assays / methods*

Substances

  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Deoxycytidine
  • Irinotecan
  • gemcitabine
  • Cisplatin
  • Fluorouracil
  • Camptothecin