Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single-Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate.
Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single-Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate.
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DOI：
10.1002/jcph.1703
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发表时间：
2021-01
影响因子：
2.9
通讯作者：
DiCioccio AT
中科院分区：
文献类型：
--
作者：
Paccaly AJ;Kovalenko P;Parrino J;Boyapati A;Xu C;van Hoogstraten H;Ishii T;Davis JD;DiCioccio AT
我们评估了血清中白细胞介素-6（IL-6）、可溶性IL-6受体和C反应蛋白（CRP）的药代动力学（PK）、药效学（PD）和PK/PD关系，皮下sar与静脉内托珠单抗单次给药后血液中的中性粒细胞绝对计数（ANC）（NCT 02097524），其来自对甲氨蝶呤（MTX）应答不足且接受稳定剂量MTX的类风湿性关节炎（RA）患者。RA患者随机（1：1：1：1）接受sar（150或200 mg皮下注射）或托珠单抗（4或8 mg/kg静脉注射）单次给药（n = 101），并在给药后6周内评估PK、PD和PK/PD关系和安全性。通过平行的线性和非线性靶向介导的清除途径描述两种药物的PK特征。无论剂量或给药途径如何，PD标志物在给药后第1周显示出相似的起效。CRP和ANC降低，CRP的中位给药后最低值为7 - 15天，ANC为3 - 5天。低剂量和高剂量的两种药物在给药后2周内达到了相同的ANC最低值，并恢复至基线水平，表明效果饱和。sar和tocilizumab的安全性特征基本相似。总之，尽管PK存在差异，但皮下注射sar和静脉注射托珠单抗单次给药后CRP（疗效）和ANC（安全性）降低的开始时间相似。PD效果和安全性与之前的研究一致。
We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin‐6 (IL‐6), soluble IL‐6 receptor, and C‐reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single‐dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target‐mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7‐15 days for CRP and 3‐5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.
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DOI：
10.1016/s0140-6736(18)32203-7
发表时间：
2018-11-10
期刊：
Lancet (London, England)
影响因子：
--
作者：
GBD 2017 Causes of Death Collaborators
通讯作者：
GBD 2017 Causes of Death Collaborators
影响因子：
6.2
作者：
Gabay C;Msihid J;Zilberstein M;Paccard C;Lin Y;Graham NMH;Boyapati A
通讯作者：
Boyapati A
DOI：
10.1093/rheumatology/kez265
发表时间：
2020-02-01
期刊：
Rheumatology (Oxford, England)
影响因子：
--
作者：
Fleischmann R;Genovese MC;Lin Y;St John G;van der Heijde D;Wang S;Gomez-Reino JJ;Maldonado-Cocco JA;Stanislav M;Kivitz AJ;Burmester GR
通讯作者：
Burmester GR
影响因子：
20.3
作者：
Nishimoto, Norihiro;Terao, Kimio;Kakehi, Takahiro
通讯作者：
Kakehi, Takahiro
影响因子：
3.7
作者：
Bay-Jensen, Anne C.;Wichuk, Stephanie;Maksymowych, Walter P.
通讯作者：
Maksymowych, Walter P.