Dumortier Thomas, Valenzuela Guillermo, Churchill Melvin, Mijatovic Jelena, Bruin Gerard, Pricop Luminita, Richards Hanno, Renard Didier, Singhal Atul, Marathe Anshu
Novartis Pharma AG, Basel, Switzerland.
Integral Rheumatology & Immunology Specialists, Plantation, Florida, USA.
Clin Pharmacol Ther. 2025 Aug;118(2):480-488. doi: 10.1002/cpt.3716. Epub 2025 Jun 2.
The objective of this modeling and simulation analysis was to determine an intravenous (IV) secukinumab dosing regimen with steady-state exposure within the ranges of the approved subcutaneous (SC) regimens (300 and 150 mg every 4 weeks [q4w]) and to predict the efficacy and safety of this IV regimen for patients with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA). This approach was suggested by the US Food and Drug Administration (FDA) following review of the primary endpoint analysis results of secukinumab 3 mg/kg q4w IV in patients with PsA (INVIGORATE-2 study). Noting the higher exposure of the investigated IV regimen compared to the approved SC regimens, the FDA considered that the INVIGORATE-2 data available through Week 16 only may not convey sufficient safety information to support the benefit-risk assessment of this IV regimen. A population pharmacokinetic (popPK) analysis was conducted on a pool of 15 PsA or axSpA clinical trials to identify 1.75 mg/kg IV secukinumab q4w (with or without a 6 mg/kg IV loading dose at Week 0) as a regimen with steady-state exposure within the ranges of the approved SC regimens. This entitled its efficacy and safety to be assessed by full extrapolation from those of the approved SC regimens. This extrapolation was substantiated by the use of exposure-response analyses to predict the efficacy and safety of the IV regimen. Based on those analyses, this IV secukinumab regimen, not tested in clinical trials, was approved by the FDA for the treatment of patients with PsA and axSpA.
本建模与模拟分析的目的是确定一种静脉注射（IV）司库奇尤单抗给药方案，使其稳态暴露量处于已批准的皮下注射（SC）方案（每4周300和150mg [q4w]）范围内，并预测该静脉注射方案对银屑病关节炎（PsA）或中轴型脊柱关节炎（axSpA）患者的疗效和安全性。美国食品药品监督管理局（FDA）在审查司库奇尤单抗3mg/kg q4w静脉注射治疗PsA患者的主要终点分析结果（INVIGORATE - 2研究）后提出了这种方法。注意到所研究的静脉注射方案与已批准的皮下注射方案相比暴露量更高，FDA认为仅第16周前可得的INVIGORATE - 2数据可能无法传达足够的安全信息以支持该静脉注射方案的获益 - 风险评估。对15项PsA或axSpA临床试验的数据池进行了群体药代动力学（popPK）分析，以确定1.75mg/kg静脉注射司库奇尤单抗q4w（第0周有或无6mg/kg静脉注射负荷剂量）作为一种稳态暴露量处于已批准皮下注射方案范围内的方案。这使其疗效和安全性可通过从已批准皮下注射方案进行完全外推来评估。通过使用暴露 - 反应分析来预测静脉注射方案的疗效和安全性，证实了这种外推。基于这些分析，这种未在临床试验中测试过的静脉注射司库奇尤单抗方案被FDA批准用于治疗PsA和axSpA患者。
