PI-036 - AN IN SILICO SIMULATION STUDY OF EXTENDED INTERVAL DOSING OF ATEZOLIZUMAB USING POPULATION PHARMACOKINETICS.

C. Peer¹, K. Schmidt¹, O. Arisa¹, W. Richardson¹, K. Paydary², D. Goldstein^3,4,5, W. Figg¹, M. Ratain²; ¹National Cancer Institute, Bethesda, MD, USA, ²The University of Chicago, Chicago, IL, USA, ³Tel Aviv University, Tel Aviv, Israel, ⁴Davidoff Cancer Center, Rabin Medical Center, Tel Aviv, Israel, ⁵Clalit Health Services, Tel Aviv, Israel.

Background: Atezolizumab (Tecentriq®) is approved for use as 1200 mg every 3 weeks (q3w), 840 mg q2w or 1680 mg q4w; however all these regimens result in excessive steady-state trough concentration (CMIN,SS) beyond the target concentration of 6 g/mL reported by the sponsor. In this in silico population PK (PPK) simulation study, various extended dosing regimens were explored.

Methods: After generating a virtual patient (VP) dataset (n=1000) using R v4.1.3, various extended regimens were simulated using a PPK model that incorporated time-varying clearance. The optimal regimen selected is based on maintaining the target CMIN,SS of 6 g/mL in ≥95% of virtual patients. Then, two loading doses of the three approved regimens -840 mg q2w, 1200 mg q3w or 1680 mg q4w- were simulated, followed by the extended 840 mg q6w regimen through 7 cycles. Weekly steady-state AUC and CMIN,SS were output for comparative statistics. Additionally, a univariate exposure-response (E-R) logistic regression model for adverse events of special interest (AESI) was duplicated from the FDA CDER review, and used to predict probability of AESI by predicted AUCSS at cycle 7 from 840 mg q6w.

Results: 840 mg q6w maintained target CMIN,SS in > 99% of VPs. In all three scenarios, >99% of VPs maintained cycle 7 CMIN,SS above 6 g/mL: 8.7 g/mL, 7.4 g/mL or 6.9 g/mL, after two loading doses of each 840 mg q2w, 1200 mg q3w or 1680 mg q4w regimens, followed by 840 mg q6w in all three scenarios, respectively. AUCSS from 840 mg q6w resulted in a non-significant (p=0.63) E-R relationship with AESI.

Conclusion: The extended regimen of 840 mg q6w can maintain therapeutic CMIN,SS of 6 g/mL at steady-state in 99% of VPs, while reducing the probability of AESI. This atezolizumab dose re-optimization is currently being investigated as an upcoming clinical trial.