Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib

Abstract

Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single-dose pharmacokinetics (PK) of cabozantinib in renally or hepatically impaired subjects. Study 1 enrolled 10 subjects, each with mild or moderate impairment of renal function; 12 healthy subjects were matched to the moderate group for age, sex, and body mass index (BMI). Study 2 enrolled 8 males each with mild or moderate hepatic impairment; 10 healthy males were matched to the moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21 days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0-∞ for impaired to normal organ function cohorts were (1) approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and moderate hepatic impairment, respectively. The percentage of unbound drug was slightly higher in both moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or moderate renal impairment. Subjects with mild or moderate hepatic impairment administered cabozantinib should be monitored closely for potential treatment-emergent drug toxicity that may necessitate a dose hold or reduction.

Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study

“…In a separate study of subjects with hepatic impairment, geometric least squared mean ratios for plasma cabozantinib AUC 0-inf for impaired to normal organ function cohorts were ∼81% and ∼63% higher in subjects with mild and moderate hepatic impairment, respectively [26]. …”

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines

“…With the impaired subject treated as the reference subject, the control is matched for demographic and anthropometric measures such as race, age, body weight and/or BMI to be within some reasonable range of the reference individual. Neither the EMA nor FDA guidelines codify a particular range for age and weight; however, our experience matching controls to the reference impaired age ±10 years and BMI ±5-20% is reasonable to recruit and have supported labeling [32,66] Use of tobacco products, when permitted by protocol, should also be considered when matching control subjects to impaired, as smoking in particular, has been demonstrated to influence GFR in both healthy and renal impaired individuals, as address in Section 6.4.…”

“…A loading dose strategy might be considered to expedite reaching steady state if the elimination half-life is relatively long, necessitating repeat dosing for several weeks. However, if a drug with a long half-life can achieve clinically relevant concentrations following single dose administration, administering a loading doses or assessing the pharmacokinetic impact at steady-state may not be necessary [32]. In addition, a loading dose could be considered for drugs intended to be administered as an IV infusion [33].…”

Cabozantinib for the treatment of renal cell carcinoma

“…Within a 48-day collection period after a single oral dose of 14 C-cabozantinib in healthy subjects, approximately 81% of the total administered radioactivity was recovered with 54% in feces and 27% in urine [26]. Exposure (AUC 0-inf ) was approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, compared to subjects with normal renal function [27]. Exposure (AUC 0-inf ) to cabozantinib was increased by about 81% and 63% in subjects with mild and moderate hepatic impairment, respectively, compared to subjects with normal hepatic function.…”