The impact of hepatic and renal function on panitumumab exposures in patients with metastatic RAS wild-type colorectal cancer

Abstract

Purpose: Panitumumab is a human monoclonal antibody targeting the epidermal growth factor receptor for the treatment of wild-type RAS metastatic colorectal cancer (mCRC). Currently, no dedicated clinical studies have evaluated the effect of organ impairment on the pharmacokinetics of panitumumab. Here, we present data from late phase studies of panitumumab in patients with mCRC and analyses of the effect of hepatic or renal impairment on the exposure of panitumumab.

Methods: From three multicenter, open-label, phase 2 and phase 3 studies, 349 and 351 patients were included in hepatic and renal function subgroup analyses, respectively. Patients who received IV panitumumab and serum exposures were compared to patients with varying degrees of hepatic and renal organ dysfunction.

Results: The Cmax and Ctrough values for patients with mild (n = 119) and moderate (n = 4) hepatic impairment were within the range of serum concentrations of panitumumab for the normal hepatic function subgroup. The distributions of serum concentration of panitumumab in patients with mild (n = 85) or moderate (n = 19) renal impairment were similar to the serum concentrations of panitumumab in the normal renal function subgroup. Population pharmacokinetic modeling and covariate analysis results were also consistent with lack of any significant effect of renal or hepatic impairment on the pharmacokinetics of panitumumab. Additionally, real-world evidence from case studies of patients with mCRC and severe hepatic or renal impairment, which is a rare patient population to study, indicated lack of clinically relevant differences in exposure of panitumumab compared with patients with mCRC and normal hepatic or renal function.

Conclusions: Mild-to-moderate hepatic or renal dysfunction had no clinically meaningful impact on the pharmacokinetics of panitumumab in patients with mCRC. No dose adjustments for panitumumab are warranted in patients with mCRC with mild-to-moderate hepatic or renal dysfunction.

Trial registration: ClinicalTrials.gov; NCT00083616, NCT00089635, NCT00113763.

Keywords: Dose adjustment; Hepatic impairment; Panitumumab; Pharmacokinetics; RAS wild-type; Renal impairment.

Conflict of interest statement

Michael Z. Liao was an employee of and stockholder of Amgen. Hans Prenen has received honoraria and/or travel grants from Amgen, Bayer, Ipsen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Terumo, and Vifor Pharma. Sandeep Dutta and Vijay V. Upreti are employees of and stockholders in Amgen.

© 2021. The Author(s).

Figures

Fig. 1

Cmax (a) and Ctrough (b) in patients with varying degrees of hepatic dysfunction on week 7 before and after intravenous infusion of panitumumab at 6 mg/kg every 2 weeks. The "box" in the plot shows the median as a line and the first (25th percentile) and third quartile (75th percentile) of the distribution as the lower and upper parts of the box. The “whiskers” (error bars) above and below the box indicate the 90th and 10th percentiles. The horizontal lines above and below the whiskers are outliers. Cmax, maximum serum concentration; Ctrough, trough serum concentration

Fig. 2

Cmax (a) and Ctrough (b) in patients with varying degrees of renal dysfunction on week 7 before and after intravenous infusion of panitumumab at 6 mg/kg every 2 weeks. The “box” in the plot shows the median as a line and the first (25th percentile) and third quartile (75th percentile) of the distribution as the lower and upper parts of the box. The “whiskers” (error bars) above and below the box indicate the 90th and 10th percentiles. The horizontal lines above and below the whiskers are outliers. Cmax, maximum serum concentration; Ctrough, trough serum concentration

Fig. 3

Plot of inter-patient random effect (ETA1) on volume of central compartment (V1) versus covariates (Top Row: base model, Bottom Row: Final model). A reference line at y = 0 and local regression smoother trend lines have been included. Panels from the left: ETA1 versus body weight in kg (WT), ETA1 versus ALT concentration in U/L (AST), ETA1 versus AST concentration in U/L (ALT), and ETA1 versus creatinine clearance in mL/min (CLCR)

Fig. 4

Plot of inter-patient random effect (ETA3) on clearance (CL) versus covariates (Top Row: base model, Bottom Row: final model). A reference line at y = 0 and local regression smoother trend lines have been included. Panels from the left: ETA3 versus body weight in kg (WT), ETA3 versus ALT concentration in U/L (AST), ETA3 versus AST concentration in U/L (ALT), and ETA3 versus creatinine clearance in mL/min (CLCR)