Flat dose regimen of toripalimab based on model-informed drug development approach

Lili Li; Jianye Qu; Ming Song; Qun Zhao; Yonghua Yang; Xi Tan; Yanyan Hu; Jing Li; Yunfei Lin; Hui Feng; Sheng Yao; Patricia Keegan; Meixia Chen

doi:10.3389/fphar.2022.1069818

Flat dose regimen of toripalimab based on model-informed drug development approach

Front Pharmacol. 2023 Jan 13:13:1069818. doi: 10.3389/fphar.2022.1069818. eCollection 2022.

Authors

Lili Li¹, Jianye Qu¹, Ming Song¹, Qun Zhao¹, Yonghua Yang¹, Xi Tan¹, Yanyan Hu¹, Jing Li¹, Yunfei Lin¹, Hui Feng^{1

2}, Sheng Yao^{1

2}, Patricia Keegan², Meixia Chen¹

Affiliations

¹ Shanghai Junshi Biosciences, Shanghai, China.
² TopAlliance Biosciences, Rockville, MD, United States.

Abstract

Introduction: Flat dosing regimen has recently been approved for programmed death receptor-1 (PD-1) inhibitors including toripalimab, nivolumab and pembrolizumab. The objective of this study is to provide pharmacological evidence for a flat dosing regimen of toripalimab by assessing the efficacy and safety profile of a 240 mg Q3W flat dose relative to the currently approved 3 mg/kg Q2W. Methods: A population pharmacokinetic (PopPK) model was established based on 1,014 evaluable patients in 13 clinical studies. The exposure-objective response rate (ORR, n = 234) and exposure-safety (n = 152) analyses were performed by logistic regression. Three safety endpoints including grade ≥ 3 adverse events (AEs), treatment-related grade ≥ 3 AEs, and AEs leading to study drug discontinuation were evaluated. Progression-free survival (PFS, n = 234) was evaluated using a Cox proportional hazard model with the Kaplan-Meier survival curve. Results: The PK profiles of toripalimab are best described by a two-compartment model with time-varying clearance characterized by a sigmoidal maximum effect (E_max) function. Simulations for the first dose and steady-state exposures for the 240 mg Q3W dosing regimen were comparable to those for the 3 mg/kg Q2W dosing regimen with 95% exposure coverage ranging from 88% to 96%. The exposure-safety analysis showed that the probability of an adverse event occurring did not increase with increases in toripalimab exposure. A flat exposure-response relationship for ORR was identified. The Kaplan-Meier survival curve showed that exposure was a predictor for PFS; however, no difference in treatment benefit was demonstrated across exposure quantiles using a Cox proportional hazard model. Discussion: This study revealed that toripalimab exposure of 240 mg Q3W dosing regimen was comparable to 3 mg/kg Q2W dosing regimen. The safety and efficacy E-R results of 240 mg Q3W is flat. Hence, the 240 mg Q3W dosing regimen is determined to be a preferred therapeutic dosage for toripalimab due to the convenience of flat dose.

Keywords: exposure-response analysis; flat dose; model-informed drug development approach; population pharmacokinetics; toripalimab.