Weight-Based Pembrolizumab Dosing at 4 mg/kg Every 6 Weeks Leads to Exposures Below Approved Doses with Unestablished Efficacy: A Pharmacokinetic Model-Based Simulation Analysis.

backgroundPembrolizumab is approved globally at a dose of 200 mg every 3 weeks (Q3W) or 400 mg every 6 weeks (Q6W) intravenously (IV). These dosing recommendations are based on established regimens that have demonstrated efficacy in clinical trials. Recently, pembrolizumab dosing at 4 mg/kg Q6W has been suggested as an alternative regimen; however, efficacy has not been evaluated in any prospective, controlled clinical trial.

objectiveThe objective was to describe the pharmacokinetic model-based analyses of pembrolizumab 4 mg/kg Q6W IV compared with approved dosing regimens. PATIENTS AND

methodsThe pharmacokinetic profiles for pembrolizumab were simulated for 4 mg/kg Q6W, 400 mg Q6W, 200 mg Q3W, and 2 mg/kg Q3W IV in 3607 participants from clinical trials of pembrolizumab across tumor types and were based on an established pharmacokinetic model informed by extensive clinical data that supported the approved pembrolizumab IV doses. Pharmacokinetic exposure measures evaluated were trough concentration (C

resultsPembrolizumab 4 mg/kg Q6W IV resulted in C

conclusionsPharmacokinetic modeling suggests pembrolizumab 4 mg/kg Q6W IV results in reduced exposures with an uncertain impact upon efficacy. Participants with lower body weight were increasingly impacted, with meaningful exposure reductions below the clinically established threshold doses of 400 mg Q6W, 200 mg Q3W, and 2 mg/kg Q3W IV. In the absence of robust clinical data on pembrolizumab efficacy at doses with exposures below those of the approved dosing regimens, weight-based dosing at 4 mg/kg Q6W poses a potential risk to treatment efficacy.