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

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.

Keywords: Cabozantinib; Cancer types; Population pharmacokinetics.

Conflict of interest statement

Conflict of interest

Steven Lacy and Linh Nguyen are stockholders and current employees of Exelixis, Inc. Dale Miles was an employee of Exelixis, Inc. when this work was performed, and is currently employed at Genentech, Inc. Jace Nielsen, Bei Yang, and Matt Hutmacher are employees of Ann Arbor Pharmacometrics Group (A2PG), Inc. who designed and conducted the popPK modeling reported in this manuscript and was funded by Exelixis, Inc. Bei Yang is currently employed by Luoxin Biotechnology (Shanghai) Co., Ltd. The authors contributed significantly to the design, conduct, analyses, and interpretation of the data, and were involved in the preparation, review, and approval of this manuscript.

Ethical approval

The clinical studies were conducted in accordance with the World Medical Association Declaration of Helsinki, the International Conference on Harmonisation Tripartite Guideline for Good Clinical Practice, and all applicable local regulations. Study protocols and informed consent documents were reviewed and approved by the Institutional Review Board (IRB) of participating institutions, and informed consent was obtained from all participants before any study-specified procedures were undertaken.

Figures

Fig. 1

Comparison of goodness-of-fit plots for patients with medullary thyroid cancer on day 1 and day 29 of study XL184-301. Solid blue, red-dashed, and green-dashed lines correspond to geometric mean observed, typical individual predicted (PREDs), and individually predicted (IPREDs) concentrations, respectively

Fig. 2

Inter-individual random effect (Eta) on CL/F versus subject population. The boxes represent median and 25th and 75th percentiles. The bars represent 5th and 95th percentiles The open circles represent individual values outside the 5th and 9th percentiles. CL clearance, CRPC castrate-resistant prostate cancer, GB glioblastoma multiforme, HV healthy volunteer, MTC medullary thyroid cancer, OTH other cancer types in Study XL184-001, POP population, RCC renal cell carcinoma

Fig. 3

Impact of covariates on steady-state cabozantinib CL/F, Cmin and Cmax relative to a reference White, male, 80 kg, 60 year-old healthy subject. CL/F, apparent clearance, Cmax,ss maximum plasma concentration at steady state, Cmin,ss minimum plasma concentration at steady state, CRPC castrate-resistant prostate cancer, GB glioblastoma multiforme, HAGE a 79-year-old subject, HWT a subject with body weight of 112 kg, LAGE a 36-year-old subject, LWT a subject with body weight of 56 kg, MTC medullary thyroid cancer, RCC renal cell carcinoma