Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors

Abstract

Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies. Identified effects of sex, baseline Eastern Cooperative Oncology Group performance status, measures of renal and hepatic function, tumor type and burden, and prior ipilimumab treatment on pembrolizumab exposure were modest and lacked clinical significance. Furthermore, simulations demonstrated the model has robust power to detect clinically relevant covariate effects on clearance. These results support the use of the approved pembrolizumab dose of 2 mg/kg every 3 weeks without dose adjustment in a variety of patient subpopulations.

Figure 1

Predicted pembrolizumab concentration‐time profiles during multiple dosing with the regimens included in the clinical studies for melanoma and non‐small cell lung cancer. Q2W, every 2 weeks; Q3W, every 3 weeks.

Figure 2

Visual predictive check for (a) 2 mg/kg every 3 weeks (Q3W) dosing group trough concentrations, (b) 10 mg/kg every 2 weeks (Q2W) dosing group trough concentrations, (c) 10 mg/kg every 2 weeks (Q2W) dosing group trough concentrations, (d) 2 mg/kg every 3 weeks (Q3W) dosing group postdose concentrations, (e) 10 mg/kg every 2 weeks (Q2W) dosing group postdose concentrations, (f) 10 mg/kg every 3 weeks (Q3W) dosing group postdose concentrations, and (e) all other samplings concentrations. Black circles represent observations; solid black lines represent median of observations; dashed lines span medians of the 90% confidence interval (CI) of observations; and the gray area represents 90% CI of the median.

Figure 3

Magnitude of exposure effects on the area‐under‐the curve (AUC) geometric mean ratio (GMR) for statistically significant covariates on clearance (CL) in the final model. The dashed vertical line represents the GMR for a typical AUC value. Circles represent the GMR for the AUC given certain covariate values, with error bars denoting the 95% confidence interval (CI) of the GMR estimate. The gray region illustrates the clinical equivalence range that extends from a GMR of 0.5–5.0. All visual predictive checks (VPCs) were performed with six bins of equal width based on the independent variable.14, 15 ALB, albumin; BSLD, baseline tumor burden; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; eGFR, estimated glomerular filtration rate; IPI, ipilimumab; NSCLC, non‐small cell lung cancer.