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
Keywords
Related Articles
- EP ID EP682048
- DOI 10.1208/ps040442
- Views 59
- Downloads 0
Role of Physiological Intestinal Water in Oral Absorption
Water volume has impact when the compound has low aqueous solubility. For example, the absorption of compounds with a Biopharmaceutics Classification System class 2 or 4 is likely to be solubility-limited. Provided the f...
Sequential Bioequivalence Trial Designs with Increased Power and Controlled Type I Error Rates
The online version of this article (doi:10.1208/s12248-013-9475-5) contains supplementary material, which is available to authorized users.
Assessment of Juvenile Pigs to Serve as Human Pediatric Surrogates for Preclinical Formulation Pharmacokinetic Testing
Pediatric drug development is hampered by biological, clinical, and formulation challenges associated with age-based populations. A primary cause for this lack of development is the inability to accurately predict ontoge...
Hemoglobin-derived Peptides as Novel Type of Bioactive Signaling Molecules
Most bioactive peptides are generated by proteolytic cleavage of large precursor proteins followed by storage in secretory vesicles from where they are released upon cell stimulation. Examples of such bioactive peptides...
Comparative In Silico–In Vivo Evaluation of ASGP-R Ligands for Hepatic Targeting of Curcumin Gantrez Nanoparticles
The online version of this article (doi:10.1208/s12248-013-9474-6) contains supplementary material, which is available to authorized users.