群体药代动力学和暴露-反应模型模拟：预测中度至重度活动性类风湿关节炎患者每6周或8周静脉注射戈利木单抗维持剂量时的暴露量和疗效。

Population Pharmacokinetic and Exposure-Response Model Simulations: Predicted Exposure and Efficacy for Maintenance Doses of Intravenous Golimumab Every 6 or 8 Weeks in Patients With Moderately to Severely Active Rheumatoid Arthritis.

作者信息

Lee Jong Bong, Broadwell Aaron, Fan Yijun, Hu Chuanpu, Adedokun Omoniyi J, Chakravarty Soumya D, Zhou Honghui, Xu Zhenhua, Leu Jocelyn H

机构信息

Janssen Research & Development, LLC, Spring House, PA, USA.

Rheumatology and Osteoporosis Specialists, Shreveport, LA, USA.

出版信息

Clin Ther. 2022 Mar;44(3):457-464.e2. doi: 10.1016/j.clinthera.2022.01.015. Epub 2022 Feb 17.

DOI:10.1016/j.clinthera.2022.01.015

PMID:35183373

Abstract

PURPOSE

Golimumab is approved to treat moderate-to-severe active rheumatoid arthritis when given intravenously at weeks 0 and 4, then every 8 weeks (Q8W) with concomitant methotrexate. These analyses assessed whether a shorter dosing interval could ameliorate diminished efficacy experienced by a small proportion of patients toward the end of the dosing interval.

METHODS

Population pharmacokinetic and exposure-response modeling simulations were performed for intravenous golimumab 2 mg/kg at weeks 0 and 4, then Q8W or every 6 weeks (Q6W) through 1 year. A 2-compartment pharmacokinetic model with linear clearance developed based on GO-FURTHER (A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, an Anti-TNFα Monoclonal Antibody, Administered Intravenously, in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy) study data was used for pharmacokinetic simulations. A latent-variable indirect exposure-response model developed based on GO-FURTHER American College of Rheumatology (ACR) 20%/50%/70% improvement (ACR20, ACR50, and ACR70, respectively) data was used to predict clinical endpoints of ACR20/ACR50/ACR70 response rates.

FINDINGS

For Q6W and Q8W dosing, respectively, predicted median golimumab steady-state trough (C) concentrations were 0.57 and 0.24 µg/mL, and C at steady state values were 33.1 and 32.9 µg/mL. Predicted peak median ACR20 steady-state response rates were 76.7% (Q6W) and 75.6% (Q8W). Predicted median ACR20 response rates at C increased by 4.7 percentage points with Q6W (73.7%) versus Q8W (69.0%) dosing. Greater improvement in ACR20 response rates at trough time points was predicted in patients with lower golimumab trough serum concentrations. Consistent findings were observed for ACR50/ACR70 response rates.

IMPLICATIONS

These simulations suggest that intravenous golimumab Q6W dosing increases golimumab C, which may improve clinical response in the small proportion of patients with rheumatoid arthritis with waning efficacy at the end of the standard dosing interval.

CLINICALTRIALS

gov identifier: NCT00973479. Clinicaltrialsregister.eu: EudraCT 2008-006064-11.

摘要

目的

戈利木单抗被批准用于治疗中度至重度活动性类风湿性关节炎，给药方案为在第0周和第4周静脉注射，随后每8周一次（Q8W），同时服用甲氨蝶呤。这些分析评估了缩短给药间隔是否可以改善一小部分患者在给药间隔末期出现的疗效降低的情况。

方法

进行群体药代动力学和暴露-反应建模模拟，静脉注射戈利木单抗2mg/kg，在第0周和第4周给药，随后1年内每8周一次（Q8W）或每6周一次（Q6W）。基于GO-FURTHER（一项多中心、随机、双盲、安慰剂对照试验，研究在接受甲氨蝶呤治疗的活动性类风湿性关节炎患者中静脉注射抗TNFα单克隆抗体戈利木单抗）研究数据开发的具有线性清除率的二室药代动力学模型用于药代动力学模拟。基于GO-FURTHER美国风湿病学会（ACR）20%/50%/70%改善率（分别为ACR20、ACR50和ACR70）数据开发的潜在变量间接暴露-反应模型用于预测ACR20/ACR50/ACR70反应率的临床终点。

结果

对于Q6W和Q8W给药，预测的戈利木单抗稳态谷浓度中位数分别为0.57和0.24μg/mL，稳态时的C值分别为33.1和32.9μg/mL。预测的ACR20稳态反应率峰值中位数分别为76.7%（Q6W）和75.6%（Q8W）。与Q8W（69.0%）给药相比 Q6W（73.7%）给药时，预测的C值下ACR20反应率中位数增加4.7个百分点。在戈利木单抗谷血清浓度较低的患者中，预测在谷时间点ACR20反应率有更大改善。ACR50/ACR70反应率也观察到一致的结果。