Modelling the effect of Sunitinib given alone and in combination with CPT-11 on the tumor growth in xenografted mice
L. Carrara (1), B. Ribba (2), M. Tod (3), M. Wei (4), B. You (5), G. Freyer (5), P. Magni (1)
(1) Dipartimento di Ingegneria Industriale e dell’Informazione, Università degli Studi di Pavia, Pavia, Italy, (2) INRIA Grenoble Rhône-Alpes, Montbonnot-Saint-Martin, Grenoble, France, (3) EMR3738, Université Claude Bernard Lyon-1, France, (4) CellVax Laboratory facility, Bâtiment Marcenac, aile Est, Ecole Nationale Vétérinaire d’Alfort, 7 avenue du Général de Gaulle, 94704 Maisons Alfort cedex, France, (5) EMR UBCL/HCL 3738; Université Claude Bernard Lyon-1; France; Centre d’Investigation des Thérapeutiques en Oncologie et Hématologie de Lyon (CITOHL); Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL); Service d’Oncologie Médicale Lyon, Lyon, France.
Objectives: Nowadays anti-angiogenic drugs are considered one of the cornerstone of the anticancer therapy. Limiting oxygen and nutrient supplies to tumor, angiogenesis inhibitors cause tumor stasis but they do not exert a direct tumor cells kill effect. For this reason they are usually administered in combination with chemotherapy.
The aim of this work is to study the effects of Sunitinib on tumor growth in xenograft mice both in the case of single drug experiment and in combination regimens with cytotoxic drug (CPT-11) to assess the type and the strength of the interaction.
Methods: Data were obtained from CellVax (France) and relate to 2 different experiments both on athymic nu/nu mice xenografted with human colonrectal cancer cells. When tumor volume reached 200-300mm3, the treatment started. Data were modeled starting from the Rocchetti TGI model [1].
Single agent experiment
The single agent experiment involves 1 control arm and 2 arms treated with Sunitinib following different schedules of administration. A naÏve pool analysis, considering average data, was performed in Matlab 2010a fitting simultaneously control and treated arms, while a population approach with non-linear mixed effect model was implemented in Monolix 4.3.2.
Combination experiment
The combination experiment, besides the control arm and 2 single agent arms, also involves 5 combination arms in which both Sunitinib and CPT-11 were administered to the animals. Both naÏve pool and mixed effect approaches were implemented as for the single agent experiment. The assessment of the type of interaction between the 2 drugs is mainly investigated by using the pool approach.
Results:
Single agent experiment
A modified version of the Rocchetti TGI model was proposed to describe the action of Sunitinib. In particular, an effect compartment was added to the original model because of the faster PK of Sunitinib compared to Avastin (drug used in [1]). The model successfully describes the experimental data.
Combination experiment
A joint model that integrates the action of the 2 drugs was used. Difference between model predicted tumor growth curves under the null interaction hypothesis and experimental data suggests a negative interaction between Sunitinib and CPT-11.
Conclusions: The new TGI model seems to be adequate to describe the action of Sunitinib, while the co-administration with the cytotoxic drug shows a negative interaction.
This work was supported by the DDMoRe project (www.ddmore.eu).
References:
[1] M. Rocchetti, M. Germani , F. Del Bene, I. Poggesi , P. Magni, E. Pesenti , G. De Nicolao.
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 Chemoterapy and Pharmacology, no 71, pp. 1147-57, 2013.
