A modeling and simulation study of less frequent dosing of nivolumab 480 mg.

Abstract

3115 Background: Nivolumab was originally approved at 3 mg/kg q2w. However, there is abundant evidence that doses as low as 0.1 mg/kg q2w are effective, and a randomized trial in RCC demonstrated equivalence across a dose range of 0.3-10 mg/kg q3w. Modeling and simulation have been used to amend the labeled dosage to 240 mg q2w or 480 mg q4w, with the latter yielding an estimated steady-state trough concentration (Ctrough) of ~50 ug/mL. Given the high cost of nivolumab and the lack of a dose-response relationship, we hypothesized that less frequent dosing of 480 mg would maintain therapeutic serum concentrations. The objective of this study was to use modeling and simulation to develop alternative dosing strategies. Methods: A simulation model was built from a published population pharmacokinetic model, incorporating time-dependent clearance. Various alternative dosing schedules were simulated, beginning with the third dose (doses 1 and 2 were 480 mg at wk 1 and 5). We conservatively chose 4.5 mg/mL as the target concentration (TC), slightly above the mean simulated Ctrough at 0.3 mg/kg q3w (4.1 ug/mL), although even lower levels are likely efficacious. The simulated dose schedules were q8w, q10w, q12w and q14w, beginning with the third dose. Simulations were performed on 50 simulated patients, with each simulation replicated 5 times. Results: The simulated Ctrough following doses 2-4 are presented in the table below. Dosing q12w should maintain TC in > 70% of patients, and q14w dosing should achieve TC in > 55% of patients. Conclusions: Modeling and simulation provide evidence that nivolumab can be effectively dosed q8-14w (after the first 2 doses), resulting in a potential 70% cost savings. As responding patients generally have a 35-45% decrease in clearance over the first 6 months of treatment, even less frequent dosing may be required for subsequent doses. Randomized trials of this interventional pharmacoeconomic strategy are indicated. Similar opportunities may exist for other checkpoint inhibitors. [Table: see text]