Pharmacodynamic modeling of chemotherapeutic effects: Application of a transit compartment model to characterize methotrexate effects in vitro
Journal Title: The AAPS Journal - Year 2002, Vol 4, Issue 4
Abstract
The time course of chemotherapeutic effect is often delayed relative to the time course of chemotherapeutic exposure. In many cases, this delay is difficult to characterize mathematically through the use of standard pharmacodynamic models. In the present work, we investigated the relationship between methotrexate (MTX) exposure and the time course of MTX effects on tumor cell growth in culture. Two cancer cell lines, Ehrlich ascites cells and sarcoma 180 cells, were exposed for 24 hours to MTX concentrations that varied more than 700-fold (0.19–140 μg/mL). Viable cells were counted on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 20, 22, and 24 for Ehrlich ascites cells and on days 1, 2, 3, 5, 7, 9, 11, 13, 14, 15, 17, 19, and 21 for sarcoma 180 cells, through the use of a tetrazolium assay. Although MTX was removed 24 hours after application, cell numbers reached nadir values more than 100 hours after MTX exposure. Data from each cell line were fitted to 3 pharmacodynamic models of chemotherapeutic cell killing: a cell cycle phase-specific model, a phase-nonspecific model, and a transit compartment model (based on the general model recently reported by Mager and Jusko, Clin Pharmacol Ther. 70:210–216, 2001). The transit compartment model captured the data much more accurately than the standard pharmacodynamic models, with correlation coefficients ranging from 0.86 to 0.999. This report shows the successful application of a transit compartment model for characterization of the complex time course of chemotherapeutic effects; such models may be very useful in the development of optimization strategies for cancer chemotherapy.
Authors and Affiliations
Evelyn D. Lobo, Joseph P. Balthasar
A thermogravimetric analysis of non-polymeric pharmaceutical plasticizers: Kinetic analysis, method validation, and thermal stability evaluation
Four non-polymeric plasticizers, propylene glycol, diethyl phthalate, triacetin, and glycerin have been subjected to rising temperature thermogravimetry for kinetic analysis and vaporization-based thermal stability evalu...
Interaction of dicaproyl phosphatidylserine with recombinant factor VIII and its impact on immunogenicity
Replacement therapy with exogenous recombinant factor VIII (rFVIII) to control bleeding episodes results in the development of inhibitory antibodies in 15% to 30% of hemophilia A patients. The inhibitory antibodies are m...
Changes in Individual Drug-Independent System Parameters during Virtual Paediatric Pharmacokinetic Trials: Introducing Time-Varying Physiology into a Paediatric PBPK Model
The online version of this article (doi:10.1208/s12248-014-9592-9) contains supplementary material, which is available to authorized users.
The joint food and agriculture organization of the united nations/world health organization expert committee on food additives and its role in the evaluation of the safety of veterinary drug residues in foods
The Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) recommended the evaluation of food additives at the international level through the establishment of an expert com...
Selectivity and potency of cyclin-dependent kinase inhibitors
Members of the cyclin-dependent kinase (CDK) family play key roles in various cellular processes. There are 11 members of the CDK family known till now. CDKs are activated by forming noncovalent complexes with cyclins su...