title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, United States of America; DMPK Modeling and Simulation, Oncology, iMED, AstraZeneca, Waltham, Massachusetts, United States of America.
authors.forename: Gary
authors.initials: G
authors.lastname: Mo
authors.affiliation: DMPK Modeling and Simulation, Oncology, iMED, AstraZeneca, Waltham, Massachusetts, United States of America.
authors.forename: Frank
authors.initials: F
authors.lastname: Gibbons
authors.affiliation: DMPK Modeling and Simulation, Oncology, iMED, AstraZeneca, Waltham, Massachusetts, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Schroeder
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krzyzanski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017239:Paclitaxel