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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Acknowledgments
The authors thank Peiming Ma, PhD, for his review and insightful comments as well as the study investigators, the clinical research support teams, and the patients who participated in the motesanib phase 2 thyroid cancer study. The authors also wish to thank Benjamin Scott, PhD (Complete Healthcare Communications, Inc., Chadds Ford, PA), and Emil Samara, PhD (PharmaPolaris, 30 Stanton Court, Danville, CA) whose work was funded by Amgen Inc., for editorial assistance in the preparation of this manuscript.
Conflict of interest
J-FL, LS, MK, RM, and Y-NS are employees of and stockholders in Amgen Inc. LC and RB are employees of Pharsight and contractors to Amgen Inc.
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J.-F. Lu and L. Claret contributed equally to this manuscript.
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Lu, JF., Claret, L., Sutjandra, L. et al. Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients. Cancer Chemother Pharmacol 66, 1151–1158 (2010). https://doi.org/10.1007/s00280-010-1456-0
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DOI: https://doi.org/10.1007/s00280-010-1456-0