Sanofi Genzyme, Bridgewater, NJ, USA.
Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA.
Clin Pharmacokinet. 2020 Nov;59(11):1451-1466. doi: 10.1007/s40262-020-00899-7.
Sarilumab is a human monoclonal antibody blocking the interleukin-6 receptor alpha (IL-6Rɑ) approved for the treatment of moderately to severely active rheumatoid arthritis in adults with inadequate response or intolerance to other disease-modifying antirheumatic drugs.
The aim of the current analysis was to describe sarilumab exposure-response relationships.
Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed describing the time course of the 28-joint disease activity score by C-reactive protein (DAS28-CRP) and absolute neutrophil count (ANC) using data from phase I-III studies (NCT01011959, NCT01061736, NCT01709578, NCT01768572) after subcutaneous sarilumab 50-150 mg every week or 100-200 mg every 2 weeks.
The time course of DAS28-CRP and ANC after sarilumab administration was described by semi-mechanistic, indirect-response models. Drug effect was predicted to be numerically greater at median exposure for the 200 mg every 2 weeks regimen versus the 150 mg every 2 weeks regimen, for both DAS28-CRP (50% vs. 47%) and ANC reduction from baseline (39% vs. 31%), with the latter showing less fluctuations within a dosing interval. Four covariates were retained in the final models: body weight, baseline rheumatoid factor status, anti-cyclic citrullinated peptide status, and concomitant methotrexate. There was no clinically meaningful influence of investigated covariates for either model.
The PopPK/PD models showed numerically greater reductions in DAS28-CRP and ANC with sarilumab 200 mg every 2 weeks than with 150 mg every 2 weeks. There was no clinically meaningful influence of investigated covariates. These data contribute to the totality of evidence that supports a sarilumab subcutaneous starting dose of 200 mg every 2 weeks, with a subsequent reduction to 150 mg every 2 weeks in the event of laboratory abnormalities such as neutropenia.
沙利鲁单抗是一种人源化单克隆抗体，可阻断白细胞介素 6 受体α（IL-6Rɑ），用于治疗对其他疾病修饰抗风湿药物反应不足或不耐受的中重度活跃性类风湿关节炎成人患者。
本分析旨在描述沙利鲁单抗的暴露-反应关系。
采用群体药代动力学/药效学（PopPK/PD）模型描述来自 I-III 期研究（NCT01011959、NCT01061736、NCT01709578、NCT01768572）的数据，描述皮下注射沙利鲁单抗 50-150mg/周或 100-200mg/2 周后 28 关节疾病活动评分（DAS28-CRP）和绝对中性粒细胞计数（ANC）的时间过程。
沙利鲁单抗给药后 DAS28-CRP 和 ANC 的时间过程由半机械、间接反应模型描述。与 150mg/2 周方案相比，200mg/2 周方案的中位暴露时，药物效应在数值上更大，DAS28-CRP（50%对 47%）和 ANC 与基线相比的降低（39%对 31%），后者在给药间隔内波动较小。最终模型中保留了 4 个协变量：体重、基线类风湿因子状态、抗环瓜氨酸肽状态和伴随的甲氨蝶呤。对于这两种模型，没有发现研究协变量有临床意义的影响。
PopPK/PD 模型显示，与 150mg/2 周方案相比，沙利鲁单抗 200mg/2 周方案可使 DAS28-CRP 和 ANC 降低程度更大。研究协变量无临床意义的影响。这些数据有助于支持沙利鲁单抗皮下起始剂量为 200mg/2 周的总体证据，随后在出现中性粒细胞减少等实验室异常时减少至 150mg/2 周。
