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

Abstract

PurposeAn 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.MethodsPlasma 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.ResultsPK 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.ConclusionThis 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.Electronic supplementary materialThe online version of this article (10.1007/s00280-018-3581-0) contains supplementary material, which is available to authorized users.

Updated Population Pharmacokinetic Model of Cabozantinib Integrating Various Cancer Types Including Hepatocellular Carcinoma

“…Transformed parameter estimates and corresponding 90%CIs are shown in Table for the updated integrated model including hepatocellular carcinoma patients and for the same model including the assessment of liver dysfunction effects on cabozantinib PK. With the addition of hepatocellular carcinoma patients, PK parameter estimates and covariate effects were similar to the previous integrated PPK model . For a white male subject, CL/F at steady state was estimated as 2.48 L/h and Vc/F as 212 L. Distributions of individual predicted CL/F and Vc/F across population are shown in Figure (A,B).…”

“…The analytical data preparation was previously described by Lacy et al with new liver dysfunction covariates defined by the NCI‐ODWG criteria . From , the classification stratifies liver dysfunction into 4 groups according to TB and AST levels: normal (TB and AST ≤ upper limit of normal [ULN]), mild (TB ≤ ULN and AST > ULN or TB > 1‐3 × ULN with any AST), moderate (TB > 1.5‐3 × ULN with any AST level), or severe (TB > 3 × ULN with any AST level).…”

“…An integrated PPK model was previously developed to characterize the cabozantinib concentration‐time profile in HV and subjects with various cancer types . The exponential relationship was applied to the model's interindividual variability for the PK parameters.…”

“…K a and relative oral bioavailability for the capsule formulation were 58% and 14% lower than the reference tablet formulation, respectively . Prespecified covariates including formulation, age, sex, race, body weight, and cancer types were included in the integrated PPK model.…”

“…9 A population pharmacokinetic (PPK) model of cabozantinib was previously developed in HV and patients with various malignancies including MTC, RCC, castration-resistant prostate cancer (CRPC), and glioblastoma multiforme. 10 Age, weight, sex, race, and cancer type were predicted to have low impact on cabozantinib apparent clearance (CL/F), except for MTC; patients with MTC show approximately 90% higher CL/F relative to HV. Cabozantinib was also studied in HV with varying degrees of liver dysfunction based on the Child-Pugh (CP) criteria.…”