Wang Lei, Liu Lixiong, Hong Xiaoping, Liu Dongzhou, Cheng Zeneng
Department of Rheumatology and Immunology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China.
Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China.
Front Pharmacol. 2021 Nov 22;12:782385. doi: 10.3389/fphar.2021.782385. eCollection 2021.
Delanzomib is a novel proteasome inhibitor initially developed for treating multiple myeloma. It was found to inhibit the expression of tumor necrosis factor alpha (TNF-α). This study aimed to investigate the ameliorating effect of delanzomib on collagen-induced arthritis (CIA) and to explore the pharmacodynamics and pharmacokinetics (PK) interactions between delanzomib and adalimumab. Rats with CIA were randomly assigned to receive the treatment with delanzomib, adalimumab, delanzomib combined with adalimumab, or placebo. Visual inspection and biochemical examinations including TNF-α, interleukin 6, and C-reactive protein were performed to assess arthritis severity during the treatment. The adalimumab concentration in rats was determined to evaluate the PK interaction between delanzomib and adalimumab. Also, the levels of neonatal Fc receptor (FcRn) and FcRn mRNA were measured to explore the role of FcRn in the PK interaction between delanzomib and adalimumab. As a result, delanzomib combined with adalimumab exhibited stronger anti-arthritis activity than a single drug because both drugs synergistically reduced TNF-α level . Delanzomib also decreased adalimumab elimination in rats by increasing the level of FcRn. The slower elimination of adalimumab in rats further prolonged the anti-TNF-α effect of adalimumab. Moreover, FcRn level was increased by delanzomib suppressing FcRn degradation rather than promoting FcRn production. In conclusion, delanzomib combined with adalimumab may be a potential therapeutic approach for treating rheumatoid arthritis. The initial finding that the PK interaction occurred between delanzomib and adalimumab may have clinical relevance for patients who simultaneously take proteasome inhibitors and anti-TNF-α therapeutic proteins.
地来佐米是一种最初开发用于治疗多发性骨髓瘤的新型蛋白酶体抑制剂。研究发现它能抑制肿瘤坏死因子α（TNF-α）的表达。本研究旨在探讨地来佐米对胶原诱导性关节炎（CIA）的改善作用，并探索地来佐米与阿达木单抗之间的药效学和药代动力学（PK）相互作用。将患有CIA的大鼠随机分为接受地来佐米、阿达木单抗、地来佐米与阿达木单抗联合治疗或安慰剂治疗的组。通过肉眼观察以及包括TNF-α、白细胞介素6和C反应蛋白在内的生化检查来评估治疗期间的关节炎严重程度。测定大鼠体内阿达木单抗的浓度以评估地来佐米与阿达木单抗之间的PK相互作用。此外，测量新生儿Fc受体（FcRn）及其mRNA的水平，以探索FcRn在地来佐米与阿达木单抗PK相互作用中的作用。结果显示，地来佐米与阿达木单抗联合使用比单一药物具有更强的抗关节炎活性，因为两种药物协同降低了TNF-α水平。地来佐米还通过提高FcRn水平降低了大鼠体内阿达木单抗的清除率。阿达木单抗在大鼠体内清除较慢进一步延长了其抗TNF-α的作用。此外，地来佐米通过抑制FcRn降解而非促进其产生来提高FcRn水平。总之，地来佐米与阿达木单抗联合使用可能是治疗类风湿性关节炎的一种潜在治疗方法。地来佐米与阿达木单抗之间发生PK相互作用这一初步发现可能对同时服用蛋白酶体抑制剂和抗TNF-α治疗性蛋白的患者具有临床意义。
