Abstract
PurposeIn 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.MethodsThis 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.ResultsThe 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.ConclusionsA 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-013-2208-8) contains supplementary material, which is available to authorized users.
Highlights
IntroductionThe use of combination therapies (administration of two or more different drugs) has become a widely adopted strategy in the treatment of patients with cancer, thanks to its advantages over single agent administrations [5]
The use of combination therapies has become a widely adopted strategy in the treatment of patients with cancer, thanks to its advantages over single agent administrations [5]
Considering the first experiment relative to Drug C1 given in combination with Gemcytabine (Experiment a), seven PD model parameters (i.e., w0, k0, k1, k1a, k1b, k2a, k2b) were fixed to the values previously estimated in [20] (Experiment 1) from the control and single agent arms
Summary
The use of combination therapies (administration of two or more different drugs) has become a widely adopted strategy in the treatment of patients with cancer, thanks to its advantages over single agent administrations [5]. The evaluation of the most promising combinations of a new compound with other anticancer agents, including those already available on the market, is become a fundamental step in early drug development for obtaining a complete description of the compound characteristics [20] For this purpose, ad-hoc in vitro and in vivo experiments, based on cell cultures and tumor-bearing animals, are routinely performed to assess if the combination has a synergistic, additive or antagonistic interaction (i.e., the effect of the combination is more/equal/less what would be as predicted from the knowledge of the monotherapies) [2, 7, 8, 11, 16]. The task becomes more complex when the evaluation has to be done in vivo, especially because it is confounded by the dynamics of the tumor growth (present in nontreated animals) and the above-mentioned approaches are only applicable to endpoints and not to time-course data
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