PMID- 36712659
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230202
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - Flat dose regimen of toripalimab based on model-informed drug development 
      approach.
PG  - 1069818
LID - 10.3389/fphar.2022.1069818 [doi]
LID - 1069818
AB  - 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.
CI  - Copyright (c) 2023 Li, Qu, Song, Zhao, Yang, Tan, Hu, Li, Lin, Feng, Yao, Keegan 
      and Chen.
FAU - Li, Lili
AU  - Li L
AD  - Shanghai Junshi Biosciences, Shanghai, China.
FAU - Qu, Jianye
AU  - Qu J
AD  - Shanghai Junshi Biosciences, Shanghai, China.
FAU - Song, Ming
AU  - Song M
AD  - Shanghai Junshi Biosciences, Shanghai, China.
FAU - Zhao, Qun
AU  - Zhao Q
AD  - Shanghai Junshi Biosciences, Shanghai, China.
FAU - Yang, Yonghua
AU  - Yang Y
AD  - Shanghai Junshi Biosciences, Shanghai, China.
FAU - Tan, Xi
AU  - Tan X
AD  - Shanghai Junshi Biosciences, Shanghai, China.
FAU - Hu, Yanyan
AU  - Hu Y
AD  - Shanghai Junshi Biosciences, Shanghai, China.
FAU - Li, Jing
AU  - Li J
AD  - Shanghai Junshi Biosciences, Shanghai, China.
FAU - Lin, Yunfei
AU  - Lin Y
AD  - Shanghai Junshi Biosciences, Shanghai, China.
FAU - Feng, Hui
AU  - Feng H
AD  - Shanghai Junshi Biosciences, Shanghai, China.
AD  - TopAlliance Biosciences, Rockville, MD, United States.
FAU - Yao, Sheng
AU  - Yao S
AD  - Shanghai Junshi Biosciences, Shanghai, China.
AD  - TopAlliance Biosciences, Rockville, MD, United States.
FAU - Keegan, Patricia
AU  - Keegan P
AD  - TopAlliance Biosciences, Rockville, MD, United States.
FAU - Chen, Meixia
AU  - Chen M
AD  - Shanghai Junshi Biosciences, Shanghai, China.
LA  - eng
PT  - Journal Article
DEP - 20230113
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9880172
OTO - NOTNLM
OT  - exposure-response analysis
OT  - flat dose
OT  - model-informed drug development approach
OT  - population pharmacokinetics
OT  - toripalimab
COIS- LL, JQ, MS, QZ, YY, XT, YH, JL, YL, HF, SY, MC were empolyed by Shanghai Junshi 
      Biosciences. HF, SY, PK were empolyed by TopAlliance Biosciences.
EDAT- 2023/01/31 06:00
MHDA- 2023/01/31 06:01
PMCR- 2023/01/13
CRDT- 2023/01/30 04:04
PHST- 2022/11/04 00:00 [received]
PHST- 2022/12/28 00:00 [accepted]
PHST- 2023/01/30 04:04 [entrez]
PHST- 2023/01/31 06:00 [pubmed]
PHST- 2023/01/31 06:01 [medline]
PHST- 2023/01/13 00:00 [pmc-release]
AID - 1069818 [pii]
AID - 10.3389/fphar.2022.1069818 [doi]
PST - epublish
SO  - Front Pharmacol. 2023 Jan 13;13:1069818. doi: 10.3389/fphar.2022.1069818. 
      eCollection 2022.