Background

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.

Objective

The aim of the current analysis was to describe sarilumab exposure–response relationships.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

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使用疾病活动性评分 28 关节 C 反应蛋白和类风湿性关节炎患者中性粒细胞绝对计数的 Sarilumab 的群体药代动力学-药效学关系。

背景

Sarilumab 是一种阻断白细胞介素 6 受体α (IL-6Rɑ) 的人单克隆抗体，被批准用于治疗对其他缓解疾病的抗风湿药物反应不足或不耐受的中度至重度活动性类风湿性关节炎成人。

客观的

当前分析的目的是描述 sarilumab 暴露-反应关系。

方法

使用 I-III 期研究的数据，开发了群体药代动力学/药效学 (PopPK/PD) 模型，描述了 C 反应蛋白 (DAS28-CRP) 和绝对中性粒细胞计数 (ANC) 的 28 关节疾病活动评分的时间过程。 NCT01011959、NCT01061736、NCT01709578、NCT01768572）皮下注射 sarilumab 每周 50–150 mg 或每 2 周 100–200 mg。

结果

通过半机械、间接反应模型描述了 sarilumab 给药后 DAS28-CRP 和 ANC 的时间进程。对于 DAS28-CRP（50% 对 47%）和 ANC 从基线降低（39% 对 47% . 31%)，后者在给药间隔内显示出较小的波动。最终模型中保留了四个协变量：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。对于任一模型，研究的协变量没有临床意义的影响。

结论

PopPK/PD 模型显示，与每 2 周 150 mg 的 sarilumab 相比，每 2 周 200 mg 的 DAS28-CRP 和 ANC 在数值上的降低更大。研究的协变量没有临床意义的影响。这些数据有助于支持所有证据，支持每 2 周 200 毫克的 sarilumab 皮下起始剂量，随后在出现实验室异常（如中性粒细胞减少症）时每 2 周减至 150 毫克。