Abstract 19P
Background
In preclinical studies to rank anticancer agents for their efficacy the delay in tumor growth after impermanent drug exposure is often used. For a more detailed description of the anticancer drug action, mathematical pharmacokinetics/pharmacodynamics (PK/PD) models were developed. Such models allow predicting tumor growth time evolution and particularly the delay for various drug dosages. Each PK/PD model is based on the mathematical formulation of the biological processes underlying the antitumor drug action. However, the parameterization and the choice of the dominant effect in the model may be ambiguous. Thus choosing the proper PK/PD model for the numerical description of the tumor growth remains a not straightforward task. In this work, we tested the performance of different PK/PD models to describe tumor volume delay.
Methods
We compared a popular TGI model (Simeoni et.al.) which is based on cytotoxic effect, and the Minimal model (MM, recently proposed by us) that incorporates both anti-angiogenic and cytotoxic effects in separate terms. All calculations were done using the SciPy package. For tests we obtained tumor growth data from different gemcitabine regimens in SHR mice with s.c. injected Ehrlich carcinoma cells.
Results
Both models well capture tumor volume delay when fitted to mean volumes in a group treated with single dose gemcitabine (i.p. 25 mg/kg) with slight difference in simulated tumor growth curves during the short period after injection. With parameters obtained above, predictions of the MM model for metronomic gemcitabine treatment group (i.p. 0.5 mg/kg, each day) were close to experimental values, while the predicted tumor growth curve by the TGI model significantly differed.
Conclusions
Our results emphasize the need of caution in the choice of the proper PK/PD model in preclinical studies, even when the model satisfactorily fits tumor growth delay. To have a predictive power the model should contain terms that adequately describe the biological mechanism of anticancer drug action.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.