In Silico Re-Optimization of Atezolizumab Dosing using Population Pharmacokinetic and Exposure-Response Simulation.

Atezolizumab, a humanized anti-PD-L1 monoclonal antibody, was initially approved in 2016, around the same time the sponsor published the minimum serum concentration to target to maintain saturation of receptor occupancy (6 μg/mL). The initially approved dose regimen of 1200 mg every 3 weeks (q3w) was subsequently modified to 840 mg q2w or 1680 mg q4w through pharmacokinetic simulations. Yet, each standard regimen yields steady-state trough concentrations (C MIN,SS ) far exceeding (∼40-fold) the stated target concentration. Additionally, steady-state AUC (AUC SS ) at 1200 mg q3w was significantly (p = 0.027) correlated with probability of adverse events of special interest (AESI) in NSCLC patients, and coupled with excess exposure, provide multiple incentives to explore alternative dose regimens to lower the exposure burden while maintaining an effective C MIN,SS . In this study, we first identified 840 mg q6w as an extended-interval regimen that could robustly maintain 6 μg/mL (≥ 99% of virtual patients [VPs; n = 1000] simulated), then applied that regimen to an approach that administers two "loading doses" of standard interval regimens for a future clinical trial aiming to personalize dose regimens. Each standard dose was simulated for two loading doses, then 840 mg q6w thereafter; all yielded cycle 7 C MIN,SS above 6 μg/mL in >99% of VPs. Further, AUC SS from 840 mg q6w resulted in a flattening (p = 0.63) of the exposure-response relationship with AESI. We next aim to verify this in a clinical trial seeking to validate extended-interval dosing in a personalized approach using therapeutic drug monitoring. This article is protected by copyright. All rights reserved.