Y. Feng, G. Bajaj, X. Wang, S. Agrawal, M. Gupta, A. Roy; Bristol-Myers Squibb, Princeton, NJ

BACKGROUND: Nivolumab is a fully human IgG4 monoclonal antibody programmed death-1 (PD-1) immune checkpoint inhibitor being developed for multiple tumor types. This analysis supports the clinical pharmacology profiling of nivolumab by characterizing the PK in subjects with solid tumors and determining covariates effects on PK parameters and exposure.
METHODS: The PK of nivolumab was described by a population pharmacokinetics (PPK) model, developed using 7,710 serum concentration values from 909 subjects with solid tumors (including melanoma, NSCLC and renal cell carcinoma) from seven clinical studies, with doses ranging from 0.1 to 20 mg/kg. The impact of the following baseline covariates on PK was assessed: body weight (BW), age, gender, GFR, race, ECOG, lactate dehydrogenase, hepatic function, baseline tumor size, tumor type, immunogenicity and PDL1 expression. The final PPK model was developed by retaining covariates that improved the Bayesian Information Criterion (BIC).
RESULTS: Nivolumab concentration-time data were well-described by a linear, two-compartment, zero order IV infusion model with first-order elimination. The mean parameter estimates of clearance (CL), volume of distribution at steady-state (Vss) and terminal half-life are 9.50 mL/h, 8.04 L, and 26.7 days, respectively. CL increases with albumin, and CL and Vss increase with increasing BW. BW normalized dosing produced approximately uniform exposures over the studied range of body weights (within ±50% difference in CL relative to subject weighted 80 kg). All the other tested covariates did not have clinically relevant (<20%) effects on nivolumab CL.
CONCLUSION: Nivolumab PK was linear, time-invariant and similar across tumor types.