Division of Bone Marrow Transplantation, Niigata University Medical and Dental Hospital, Asahimachi-dori 1-754, Chuoku, Niigata, Japan.
Int J Hematol. 2010 Jul;92(1):144-51. doi: 10.1007/s12185-010-0610-0. Epub 2010 Jun 9.
Pharmacological study is predictably effective in establishing an optimal monitoring strategy for the usage of cyclosporine A (CsA) to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation recipients. Pharmacokinetic profiling of 33 recipients administered CsA twice daily by 3-h intravenous infusion revealed that levels peaked 2-3 h after the start of infusion, and an exponential decline of CsA concentrations after the termination of infusion was observed. The correlation between the area under the curve (AUC(0-12)) and CsA concentration at various time points after infusion revealed that C (2) and C (3) correlated best with AUC(0-12) (r (2) = 0.725), while the trough concentration correlated poorly. Ex vivo T cell stimulation followed by intracellular cytokine detection with flow cytometry revealed that the capacity of T cells to produce cytokines upon stimulation was inversely proportional to the CsA concentration, and reached a minimum at about 700 ng/mL with a marginal decrease above this concentration. Extrapolation using the regression equations of this study and the data from our retrospective study leads to the assumption that the dose adjustment of CsA based on maintaining the C (3) concentration above 800 ng/mL may effectively prevent acute GVHD. To confirm this assumption, a prospective clinical study is required.
在预测性药物研究中，通过建立环孢素 A（CsA）的最佳监测策略，可有效预防异基因造血干细胞移植受者移植物抗宿主病（GVHD）。对 33 例每日两次静脉输注 3 小时 CsA 的受者进行药代动力学分析，结果显示输注开始后 2-3 小时达到峰值，输注结束后 CsA 浓度呈指数下降。输注后各时间点的 AUC（0-12）与 CsA 浓度之间的相关性表明，C（2）和 C（3）与 AUC（0-12）相关性最好（r（2）=0.725），而谷浓度相关性较差。体外 T 细胞刺激后，通过流式细胞术检测细胞内细胞因子，结果表明 T 细胞产生细胞因子的能力与 CsA 浓度呈反比，当 CsA 浓度约为 700ng/ml 时，其能力达到最低水平，在此浓度以上则略有下降。通过使用本研究的回归方程和我们回顾性研究的数据进行外推，假设基于维持 C（3）浓度高于 800ng/ml 来调整 CsA 剂量，可能有效地预防急性 GVHD。为了证实这一假设，需要进行前瞻性临床研究。
