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

Abstract

An integrated population pharmacokinetic (PPK) model was used to evaluate the effects of liver dysfunction on the pharmacokinetics (PK) of cabozantinib in patients with hepatocellular carcinoma and to determine whether clinical dosage adjustment may be necessary in this population. An integrated PPK model previously developed in healthy volunteers and patients with various cancer types was updated with cabozantinib concentration data from hepatocellular carcinoma patients in phase 2 and 3 studies (total 2023; hepatocellular carcinoma 489 patients). Covariate effects of cancer type including hepatocellular carcinoma population and liver dysfunction per the National Cancer Institute Organ Dysfunction Working Group criteria were evaluated (normal 1425; mild liver dysfunction 558; moderate/severe liver dysfunction 15/1 patients). With hepatocellular carcinoma patients, PK parameter estimates and covariate effects were similar to the previous PPK model (2 compartments with first‐ and zero‐order absorption and first‐order elimination). Only medullary thyroid cancer had appreciable PK differences from healthy volunteers. PK parameter estimates were similar with and without addition of liver dysfunction covariates. Patients with mild liver dysfunction were predicted to have minimal differences in apparent clearance of cabozantinib relative to patients with normal liver function. Therefore, no initial cabozantinib dosage adjustment is recommended for cancer patients with mild liver dysfunction. The small sample size for patients with moderate and severe liver dysfunction limited dosing recommendations in these subpopulations. The results from this PPK analysis were different from those of the single‐dose hepatic impairment study in healthy volunteers and more reflective of exposure in cancer patients following daily cabozantinib dosing.

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: a phase 2 multicenter study

“…Cabozantinib plasma concentrations fell over the course of this study, reflecting dose modifications. However, median cabozantinib plasma concentrations at Week 9 in both cohorts were comparable with those in the much larger-scale CELESTIAL study [ 19 ]. The data suggest that cabozantinib exposures in Japanese patients were comparable with those in the CELESTIAL study.…”

Dose adjustment for tyrosine kinase inhibitors in non‑small cell lung cancer patients with hepatic or renal function impairment (Review)

“…Based on a population PK analysis, no clinically significant differences in cabozantinib exposure were observed between subjects with mild HI (based on the NCI criteria) and those with NHF ( 20 ). In a HI study, the cabozantinib AUC and C max increased by 81 and 10%, respectively, in subjects with C-P A ( 21 ); for subjects with C-P B, the cabozantinib AUC increased by 63% and C max decreased by 29% ( 21 ).…”

Management of Adverse Events Associated with Cabozantinib Treatment in Patients with Advanced Hepatocellular Carcinoma

“…According to pharmacokinetic analyses of patients with HCC and other tumor types, mild hepatic impairment is predicted to have a minimal effect on cabozantinib exposure [ 40 ]; therefore, adjustment of the recommended 60-mg starting dose is not necessary for patients with Child–Pugh A liver function [ 7 , 16 ]. Data on the pharmacokinetics of cabozantinib in patients with moderate (Child-Pugh B) or severe (Child–Pugh C) hepatic impairment are limited [ 40 ].…”

“…According to pharmacokinetic analyses of patients with HCC and other tumor types, mild hepatic impairment is predicted to have a minimal effect on cabozantinib exposure [ 40 ]; therefore, adjustment of the recommended 60-mg starting dose is not necessary for patients with Child–Pugh A liver function [ 7 , 16 ]. Data on the pharmacokinetics of cabozantinib in patients with moderate (Child-Pugh B) or severe (Child–Pugh C) hepatic impairment are limited [ 40 ]. As per the US Food and Drug Administration (FDA) prescribing information, the starting dose of cabozantinib should be reduced to 40 mg in patients with moderate hepatic impairment, while cabozantinib is not recommended for patients with severe hepatic impairment [ 7 ].…”

“…According to pharmacokinetic analyses of patients with HCC and other tumor types, mild hepatic impairment is predicted to have a minimal effect on cabozantinib exposure [40]; therefore, adjustment of the recommended 60-mg starting dose is not necessary for patients with Child-Pugh A Fig. 2 liver function [7,16].…”