Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, Illinois, USA.
Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany.
Clin Transl Sci. 2022 Jan;15(1):267-278. doi: 10.1111/cts.13146. Epub 2021 Oct 27.
Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT-PsA program in two global phase III studies, which evaluated upadacitinib 15 and 30 mg q.d. The analyses described here characterized upadacitinib pharmacokinetics and exposure-response relationships for efficacy and safety endpoints using data from the SELECT-PsA studies. Upadacitinib pharmacokinetics in patients with PsA were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in patients with RA. Exposure-response relationships for key efficacy and safety endpoints were characterized using data from 1916 patients with PsA. The percentage of patients achieving efficacy endpoints at week 12 (American College of Rheumatology [ACR]50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, whereas no clear exposure-response trend was observed for ACR20 at week 12 or ACR20/50/70 at week 24 within the range of plasma exposures evaluated in the phase III PsA studies. No clear trends for exposure-response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin less than 8 g/dl, lymphopenia (grade ≥ 3), or neutropenia (grade ≥ 3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease greater than 2 g/dl from baseline at week 24. Based on exposure-response analyses, the upadacitinib 15 mg q.d. regimen is predicted to achieve robust efficacy in patients with PsA and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.
乌帕替尼是一种口服 JAK 抑制剂，已获批准用于治疗类风湿关节炎（RA），最近又获欧洲药品管理局批准用于治疗银屑病关节炎（PsA）。在两项全球 III 期研究的 SELECT-PsA 项目中已确立乌帕替尼治疗 PsA 的疗效和安全性概况，该两项研究评估了乌帕替尼 15mg 和 30mg，每日一次。本文所述的分析使用来自 SELECT-PsA 研究的数据，对疗效和安全性终点的药代动力学和暴露-反应关系进行了特征描述。通过贝叶斯群体分析方法对 PsA 患者的乌帕替尼药代动力学进行了描述，结果与 RA 患者的药代动力学相似。使用来自 1916 例 PsA 患者的数据对关键疗效和安全性终点的暴露-反应关系进行了描述。在 12 周时，达到疗效终点（ACR50 和 ACR70）的患者比例随着给药间隔内乌帕替尼平均血浆浓度的增加而增加，而在 III 期 PsA 研究评估的血浆暴露范围内，在 12 周时未观察到 ACR20 的明确暴露-反应趋势，在 24 周时也未观察到 ACR20/50/70 的明确暴露-反应趋势。在治疗 24 周后，未观察到发生肺炎、带状疱疹感染、血红蛋白<8g/dl、淋巴细胞减少症（≥3 级）或中性粒细胞减少症（≥3 级）与暴露-反应关系有明确的趋势。在 24 周时，严重感染和血红蛋白从基线下降>2g/dl 与血浆暴露呈浅相关。基于暴露-反应分析，乌帕替尼 15mg，每日一次的方案有望在 PsA 患者中实现强大的疗效，并与血红蛋白降低或严重感染发生率有限相关。
