Senior Research Investigator Bristol Myers Squibb, United States
Objectives: Nivolumab is a fully human IgG4 monoclonal antibody that selectively binds to the PD-1 membrane receptor and is indicated in the treatment of various solid tumors and hematologic malignancies. Nivolumab’s clearance (CL) was shown to be ~30% lower in patients with relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) compared to patients with solid tumors.[1] The objective of this population pharmacokinetic (PopPK) analysis was to characterize the PK of nivolumab in patients with newly diagnosed (ND) cHL relative to R/R cHL and solid tumors.
Methods: A previously established nivolumab PopPK model was updated.[1] Data from 1,485 adults with solid tumors and 311 adults with cHL (50 ND and 261 R/R) from 4 Phase 1 studies (MDX-1106-01, ONO-4538-01, MDX-1106-03, and CA209039); 4 Phase 2 studies (ONO-4538-02, CA209010, CA209063, and CA209205); and 3 Phase 3 studies (CA209017, CA209025, and CA209057) were included. The effect of patient population (R/R cHL vs ND cHL vs NSCLC as the reference) was introduced as a new covariate on CL in the final model. Nivolumab PK was described using a 2-compartment model with zero-order IV infusion and time-varying CL (NONMEM v7.4). Model evaluation was conducted by visual predictive check (VPC) with 1,000 simulated datasets obtained from the final model. The final model was then applied to predict and compare individual exposures in patients with ND cHL, R/R cHL, and solid tumors for nivolumab 240mg every 2 weeks (Q2W).
Results: Significant covariate effects were consistent with the previous analysis.[1] Covariate effects included baseline body weight, baseline glomerular filtration rate, sex, performance status, race, baseline albumin, and patient population on CL; baseline body weight and sex on volume of distribution; and performance status on EMAX for time-varying CL. VPC with prediction-corrected concentrations demonstrated final model predictions were in reasonable agreement with observed data across all patient populations. CL was determined to be ~30% lower in ND and R/R cHL relative to solid tumors at baseline and steady state, consistent with previous findings. Average steady state predictions across Cmin, Cmax, and Cavg at nivolumab 240mg Q2W were similar among ND and R/R cHL patients.
Conclusions: ND and R/R cHL patients had similar baseline and steady state CL following treatment with intravenous nivolumab. Furthermore, exposures for Cmin, Cmax, and Cavg after the first dose and at steady state were similar among cHL patient populations. These results suggest that disease stage among patients with cHL does not impact nivolumab PK.
Citations: [1] Wang, X., et al., Population Pharmacokinetics and Exposure - Safety Analyses of Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma. J Clin Pharmacol, 2019. 59(3): p. 364-373.
