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A Pharmacodynamic Model for the Time Course of Tumor Shrinkage by Gemcitabine + Carboplatin in Non–Small Cell Lung Cancer Patients

Authors' Affiliations: ¹ Department of Hematology-Oncology, National University Hospital, ² Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and ³ Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand

Requests for reprints: Lai-San Tham, Lilly-NUS Centre for Clinical Pharmacology, National University of Singapore, Level 6, Clinical Research Centre (MD 11), 10 Medical Drive, Singapore 117597, Singapore. Phone: 65-6413-9913; Fax: 65-6779-0587; E-mail: Tham_lai_san{at}lilly.com.

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.