Lifespan Based Pharmacokinetic-Pharmacodynamic Model of Tumor Growth Inhibition by Anticancer Therapeutics

Abstract

Accurate prediction of tumor growth is critical in modeling the effects of anti-tumor agents. Popular models of tumor growth inhibition (TGI) generally offer empirical description of tumor growth. We propose a lifespan-based tumor growth inhibition (LS TGI) model that describes tumor growth in a xenograft mouse model, on the basis of cellular lifespan T. At the end of the lifespan, cells divide, and to account for tumor burden on growth, we introduce a cell division efficiency function that is negatively affected by tumor size. The LS TGI model capability to describe dynamic growth characteristics is similar to many empirical TGI models. Our model describes anti-cancer drug effect as a dose-dependent shift of proliferating tumor cells into a non-proliferating population that die after an altered lifespan TA. Sensitivity analysis indicated that all model parameters are identifiable. The model was validated through case studies of xenograft mouse tumor growth. Data from paclitaxel mediated tumor inhibition was well described by the LS TGI model, and model parameters were estimated with high precision. A study involving a protein casein kinase 2 inhibitor, AZ968, contained tumor growth data that only exhibited linear growth kinetics. The LS TGI model accurately described the linear growth data and estimated the potency of AZ968 that was very similar to the estimate from an established TGI model. In the case study of AZD1208, a pan-Pim inhibitor, the doubling time was not estimable from the control data. By fixing the parameter to the reported in vitro value of the tumor cell doubling time, the model was still able to fit the data well and estimated the remaining parameters with high precision. We have developed a mechanistic model that describes tumor growth based on cell division and has the flexibility to describe tumor data with diverse growth kinetics.

Evaluation of Ceiba pentandra (L.) Gaertner bark extracts for in vitro cytotoxicity on cancer cells and in vivo antitumor activity in solid and liquid tumor models

“…Thus the effect on the reduction of body weight compared to control might be due to their tumor inhibitory property. Since increasing life span and tumor size/weight are reliable criteria for justifying the anticancer efficacy of any compound (Hollingshead 2008;Mo et al 2014), our study included survival time analysis along with tumor weight/size. All extracts met with this criterion and prolonged the life span.…”

Delay differential equations based models in NONMEM

“…The tumor growth inhibition (TGI) model has been widely used to characterize the tumor dynamics and the drug effect on tumor size [17]. The lifespan based TGI model using DDE has also been developed [1,18]. In this model, the drug effect is to shift the proliferating cells to an apoptotic population with cell death determined by its lifespan.…”

Model-Based Anticancer Effect of Botulinum Neurotoxin Type A1 on Syngeneic Melanoma Mice

“…This study used a modified Simeoni tumor growth inhibition model as a PD model for our final model build-up and we set it up based on information from the Simeoni perturbed (treated group) and unperturbed (control group) model. In the unperturbed model, tumor growth was exponential in its early phase and linear in its late phase ( Simeoni et al, 2004 ; Mo et al, 2014 ; Lixoft, 2021b , https://mlxtran.lixoft.com/model-libraries/tgi-library ; Li et al, 2016 ). Eq.…”