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Cancer Chemotherapy and Pharmacology

Published in:

01-11-2010 | Original Article

Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients

Authors: Jian-Feng Lu, Laurent Claret, Liviawati Sutjandra, Mita Kuchimanchi, Rebeca Melara, René Bruno, Yu-Nien Sun

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2010

Abstract

Objective

To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between motesanib exposure and tumor response in a phase 2 study of motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer.

Methods

Data from patients (n = 184) who received motesanib 125 mg once daily were used for population pharmacokinetic/pharmacodynamic modeling. Motesanib concentrations were fitted to a 2-compartment population pharmacokinetic model. Observed change in tumor size was the drug response measure for the pharmacodynamic model. Exposure measures in the pharmacokinetic/pharmacodynamic model included dose, plasma concentration profile, or steady-state area under the concentration versus time curve (AUC_ss). A longitudinal exposure–tumor response model of drug effect on tumor growth dynamics was used.

Results

Motesanib oral clearance in patients with medullary thyroid cancer was 67% higher than in patients with differentiated thyroid cancer patients (73.7 vs. 44 L/h). Patients’ disease type (medullary thyroid cancer vs. differentiated thyroid cancer) was the most important covariate for explaining interpatient variability in clearance. The objective response rates were 14 versus 2% for differentiated thyroid cancer and medullary thyroid cancer, respectively. Motesanib exposure measures (AUC_ss or concentration profile) were better predictors of tumor response than motesanib dose. The estimated motesanib concentration yielding tumor stasis (1.9 ng/mL) was lower than the observed trough concentrations in differentiated thyroid cancer and medullary thyroid cancer patients.

Conclusions

Differences in motesanib pharmacokinetics likely explain the difference in tumor response observed between differentiated thyroid cancer and medullary thyroid cancer patients. The population pharmacokinetic/pharmacodynamic model provides a tool for predicting tumor response to the drug to support the dosing regimen of motesanib in thyroid cancer patients.

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Title: Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients
Authors: Jian-Feng Lu
Laurent Claret
Liviawati Sutjandra
Mita Kuchimanchi
Rebeca Melara
René Bruno
Yu-Nien Sun
Publication date: 01-11-2010
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1456-0

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