Pharmacokinetic Simulation Analysis of Less Frequent Nivolumab and Pembrolizumab Dosing: Pharmacoeconomic Rationale for Dose Deescalation

Abstract

Nivolumab and pembrolizumab, anti–programmed cell death protein 1 monoclonal antibodies, have revolutionized oncology but are expensive. Using an interventional pharmacoeconomic approach, these drugs can be administered less often to reduce costs and increase patient convenience while maintaining efficacy. Both drugs are good candidates for less frequent dosing because of long half‐lives and no evidence of a relationship of dose to efficacy. Established population pharmacokinetic models for both nivolumab and pembrolizumab were used to simulate profiles for multiple dosing regimens on 1000 randomly generated virtual patients. Simulations were initially performed on standard dose regimens to validate these in silico predictions. Next, simulations of nivolumab 0.3 mg/kg every 3 weeks revealed that >95% of patients maintained ≥1.5 μg/mL at steady state, which was inferred as the minimum effective concentration (MEC) for both drugs. Various alternative dosing regimens were simulated for both drugs to determine which regimen(s) can maintain this MEC in >95% of patients. Extended dosing regimens of nivolumab 240 mg every 4 weeks and 480 mg every 8 weeks along with pembrolizumab 200 mg every 6 weeks were simulated, showing that >95% of patients maintained MEC or greater. These simulations demonstrate the potential to reduce drug exposure by at least 50%, thus substantially reducing patient visits (as well as costs), while maintaining equivalent efficacy. These models provide the scientific justification for an ongoing prospective randomized clinical trial comparing standard interval fixed dosing with extended interval fixed dosing, and ultimately an efficacy‐driven comparative trial.

REFINE (REduced Frequency ImmuNE checkpoint inhibition in cancers): A multi-arm phase II basket trial testing reduced intensity immunotherapy across different cancers

“…reducing the frequency) should be possible, without compromising outcomes. This is supported by simulation analyses for pembrolizumab and nivolumab (10).…”

Dosing Regimens of Immune Checkpoint Inhibitors: Attempts at Lower Dose, Less Frequency, Shorter Course

“…In terms of dosing intervals, prolonging the interval still maintains the pharmacodynamic parameters at effective levels. Simulated administration of nivolumab at 240mg Q4W/480mg Q8W regimen and pembrolizumab at 200mg Q6W regimen revealed that serum drug concentrations remained above the minimum effective concentration in more than 95% of patients ( 72 ). The Canadian Agency of Drugs and Technologies in Health simulated dosing regimens of pembrolizumab 4 mg/kg Q6W in patients weighing 70, 100, and 150 kg, all with trough target engagement above 97% ( 73 ).…”

Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non–small cell lung cancer after a single 200 mg administration

“…Considering the vastly increasing treatment cost using pembrolizumab and the financial burden among patients (in the Netherlands: € 29 million per year in 2016 versus €210 million per year in 2020), overdosing becomes even more highly undesirable ( 8 – 11 ). Alternative dosing strategies such as concentration-based dosing, dose banding, and weight-based dosing are suggested to be more cost-efficient than the current fixed-dose strategy ( 12 – 14 ). Therefore, it is vital to assess these alternative dosing strategies to lower the financial toxicity among patients being treated with pembrolizumab and warrant the accessibility of worldwide healthcare system.…”