A pharmacodynamic model for the time course of tumor shrinkage by gemcitabine + carboplatin in non-small cell lung cancer patients
Geoffrey
Nunns
Bioengineering Institute, University of Auckland
Model Status
This CellML model runs in PCenv and OpenCell to recreate the published results, but not COR because of the presence of the modulo operator. The maximum step size must be constrained to be 0.001 weeks or smaller, or the software will ignore the pulsatile administration of gemcitabine. This model describes the response of tumor size to administration of gemcitabine, and was based off original Berkeley Madonna code provided by the model authors.
Model Structure
ABSTRACT: PURPOSE: This tumor response pharmacodynamic model aims to describe primary lesion shrinkage in non-small cell lung cancer over time and determine if concentration-based exposure metrics for gemcitabine or that of its metabolites, 2',2'-difluorodeoxyuridine or gemcitabine triphosphate, are better than gemcitabine dose for prediction of individual response. EXPERIMENTAL DESIGN: Gemcitabine was given thrice weekly on days 1 and 8 in combination with carboplatin, which was given only on day 1 of every cycle. Gemcitabine amount in the body and area under the concentration-time curves of plasma gemcitabine, 2',2'-difluorodeoxyuridine, and intracellular gemcitabine triphosphate in white cells were compared to determine which best describes tumor shrinkage over time. Tumor growth kinetics were described using a Gompertz-like model. RESULTS: The apparent half-life for the effect of gemcitabine was 7.67 weeks. The tumor turnover time constant was 21.8 week.cm. Baseline tumor size and gemcitabine amount in the body to attain 50% of tumor shrinkage were estimated to be 6.66 cm and 10,600 mg. There was no evidence of relapse during treatment. CONCLUSIONS: Concentration-based exposure metrics for gemcitabine and its metabolites were no better than gemcitabine amount in predicting tumor shrinkage in primary lung cancer lesions. Gemcitabine dose-based models did marginally better than treatment-based models that ignored doses of drug administered to patients. Modeling tumor shrinkage in primary lesions can be used to quantify individual sensitivity and response to antitumor effects of anticancer drugs.
The original paper reference is cited below:
A pharmacodynamic model for the time course of tumor shrinkage by gemcitabine + carboplatin in non-small cell lung cancer patients, Lai-San Tham, Lingzhi Wang, Ross A Soo, Soo-Chin Lee, How-Sung Lee, Wei-Peng Yong, Boon-Cher Goh and Nicholas H.G. Holford, 2008, Clin Cancer Res, volume 14, 4213-4218. PubMed ID: 18594002
Schematic diagram of the model.
$\mathrm{Exposure}=\begin{cases}\mathrm{Dose} & \text{if $(\mathrm{time}< \mathrm{Cycle\_Int}\mathrm{N\_Cycle})\land (\mathrm{Dose\_Int1}< \mathrm{rem\_time})\land (\mathrm{rem\_time}< \mathrm{Dose\_Length})$}\\ \mathrm{Dose} & \text{if $(\mathrm{time}< \mathrm{Cycle\_Int}\mathrm{N\_Cycle})\land (\mathrm{Dose\_Int2}< \mathrm{rem\_time})\land (\mathrm{rem\_time}< \mathrm{Dose\_Int2}+\mathrm{Dose\_Length})$}\\ 0 & \text{otherwise}\end{cases}\mathrm{rem\_time}=\frac{\mathrm{time}\mathrm{conversion\_factor}\mod \mathrm{Cycle\_Int}\mathrm{conversion\_factor}}{\mathrm{conversion\_factor}}$
$\mathrm{k\_1}=\frac{\ln 2}{\mathrm{t\_half\_eq}}\frac{d \mathrm{Ce}}{d \mathrm{time}}=\frac{\mathrm{Exposure}}{1}-\mathrm{Ce}\mathrm{k\_1}\mathrm{Effect}=1-\frac{\mathrm{E\_max}\mathrm{Ce}}{\mathrm{Amt\_50}+\mathrm{Ce}}$
$\mathrm{RateIn}=\mathrm{Size\_0}\mathrm{k\_2}\mathrm{k\_2}=\frac{\ln 2}{\mathrm{T\_Turnover}}\frac{d \mathrm{Size}}{d \mathrm{time}}=(\mathrm{RateIn}\mathrm{Effect}-\mathrm{k\_2}\mathrm{Size})\mathrm{Size}$
CSLeekeyword60100000.000118594002gemcitabinecancerPKPDpharmacodynamictumourGeoffNunns421314
A pharmacodynamic model for the time course of tumor shrinkage by gemcitabine + carboplatin in non-small cell lung cancer patients
4218CBGohLWangPWYong2008-07-01HNHolfordClinical Cancer ResearchARSooThe University of AucklandAuckland Bioengineering InstituteSHLeeSLThamgnunns1@jhu.edu