Mori Shunsuke
Department of Rheumatology, Clinical Research Center for Rheumatic Disease, National Kumamoto Saishunsou Hospital, 2659 Suya, Kohshi 861-1196, Japan.
Mod Rheumatol. 2007;17(2):83-91. doi: 10.1007/s10165-006-0544-9. Epub 2007 Apr 20.
Infliximab, a chimeric anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody, has been recognized as significantly improving the course of rheumatoid arthritis (RA); however, a subset of patients shows poor responses. To understand the mechanism underlying such unresponsiveness, I examined the clinical pharmacokinetics (PK) of infliximab, using time-serum concentration profiles obtained from 21 RA patients who had received infliximab therapy in combination with methotrexate (MTX). At week 14 of therapy, 15 cases achieved good or moderate responses in the European League Against Rheumatism (EULAR) criteria, and 3 cases resulted in nonresponders. The others discontinued therapy because of severe adverse effects or aggravation of disease activities. The means of distribution volume and elimination half-life (t (1/2)) during the first 2 weeks were 0.05 l/kg and 9.5 days, respectively. Through 14 weeks, most good and moderate responders maintained serum concentrations of more than 1 microg/ml, even immediately before the next infusions. Only 3 cases among good or moderate responders showed undetectable levels of trough serum concentration at week 14. In contrast, the PK profiles of all nonresponders except one showed rapid clearance during therapy. These data support the idea that the rapid clearance of infliximab is the main cause of poor therapeutic responses. I also found that the t (1/2) during the first 2 weeks is inversely correlated to the disease activity scores for 28 joints at the start of treatment, suggesting that TNF-alpha levels may determine the disease activity of RA. For patients who showed a rapid clearance of infliximab, the increased use of prednisone or MTX was beneficial to achieve sufficient clinical responses. The addition of tacrolimus was effective to improve the clinical outcomes of nonresponders. Thus PK data apparently offer guidance when modified treatment for infliximab-resistant RA patients is being considered.
英夫利昔单抗是一种嵌合型抗肿瘤坏死因子α（TNF-α）单克隆抗体，已被公认为能显著改善类风湿关节炎（RA）的病程；然而，有一部分患者反应不佳。为了解这种无反应性的潜在机制，我使用从21例接受英夫利昔单抗与甲氨蝶呤（MTX）联合治疗的RA患者获得的时间-血清浓度曲线，研究了英夫利昔单抗的临床药代动力学（PK）。在治疗第14周时，15例患者根据欧洲抗风湿病联盟（EULAR）标准达到良好或中度反应，3例为无反应者。其他患者因严重不良反应或疾病活动加剧而停止治疗。前2周的分布容积均值和消除半衰期（t（1/2））分别为0.05 l/kg和9.5天。至14周时，大多数良好和中度反应者即使在下次输注前即刻，血清浓度仍维持在1μg/ml以上。在良好或中度反应者中，仅3例在第14周时谷血清浓度检测不到。相比之下，除1例无反应者外，所有无反应者的PK曲线在治疗期间均显示清除迅速。这些数据支持英夫利昔单抗清除迅速是治疗反应不佳的主要原因这一观点。我还发现，治疗开始时前2周的t（1/2）与28个关节的疾病活动评分呈负相关，提示TNF-α水平可能决定RA的疾病活动度。对于英夫利昔单抗清除迅速的患者，增加泼尼松或MTX的用量有助于获得充分的临床反应。添加他克莫司可有效改善无反应者的临床结局。因此，在考虑对英夫利昔单抗抵抗的RA患者进行调整治疗时，PK数据显然能提供指导。
