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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2018

Open Access 01-06-2018 | Original Article

A population pharmacokinetic model of cabozantinib in healthy volunteers and patients with various cancer types

Authors: Steven Lacy, Bei Yang, Jace Nielsen, Dale Miles, Linh Nguyen, Matt Hutmacher

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2018

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Abstract

Purpose

An integrated population pharmacokinetic (popPK) model was developed to describe the pharmacokinetics (PK) of tyrosine kinase inhibitor cabozantinib in healthy volunteers (HVs) and patients with various cancer types and to identify any differences in cabozantinib PK across these populations.

Methods

Plasma concentration data used to develop the popPK model were obtained from nine clinical trials (8072 concentrations from 1534 HVs or patients) of cabozantinib in HVs and patients with renal cell carcinoma (RCC), medullary thyroid carcinoma (MTC), glioblastoma multiforme, castration-resistant prostate cancer, or other advanced malignancies.

Results

PK data across studies were adequately characterized by a two-compartment disposition model with dual first- and zero-order absorption processes and first-order elimination. Baseline demographic covariates (age, weight, gender, race, and cancer type) were generally predicted to have a small-to-moderate impact on apparent clearance (CL/F). However, MTC cancer type did show an approximately 93% higher CL/F relative to HVs following chronic dosing, resulting in approximately 40–50% lower predicted steady-state cabozantinib plasma concentrations.

Conclusion

This popPK analysis showed cabozantinib CL/F values to be higher for patients with MTC and may account for the higher dosage required in this patient population (140-mg) to achieve plasma exposures comparable to those in patients with RCC and other tumor types administered a 60-mg cabozantinib tablet dose. Possible factors that may underlie the higher cabozantinib clearance observed in MTC patients are discussed.
Appendix
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Metadata
Title
A population pharmacokinetic model of cabozantinib in healthy volunteers and patients with various cancer types
Authors
Steven Lacy
Bei Yang
Jace Nielsen
Dale Miles
Linh Nguyen
Matt Hutmacher
Publication date
01-06-2018
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3581-0

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