Brunet M, Crespo M, Millán O, Serón D, Torregrosa V, Jiménez O, Moreso F, Martorell J, Grinyo J M, Oppenheimer F
Pharmacology Department (CDB), Hospital Clinic Barcelona, Barcelona, Spain.
Transplant Proc. 2007 Sep;39(7):2160-2. doi: 10.1016/j.transproceed.2007.07.003.
Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies.
We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC(0-12h)) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-gamma synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies.
Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng x h/mL, while C0 MPA was 1.0 microg/mL and AUC = 23.9 microg x h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 microg x h/mL) and was 48.3 microg x h/mL at 6 months. Patients with BPAR showed lower CsA AUC (P = .06) and a significantly lower baseline inhibition of calcineurin activity (P < .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 (P = .01). All biomarkers evaluated were significantly inhibited compared with the standard population.
When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg x 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.
有效预防急性排斥反应（ARE）需要在肾移植后的头几天充分使用免疫抑制治疗的各个成分。本研究的目的是根据药代动力学（PK）和药效学（PD）评估环孢素（CsA）和霉酚酸（MPA）暴露量之间的相关性，以及6个月活检证实的急性排斥反应（BPAR）发作和6个月方案活检中的慢性移植肾肾病。
我们检查了22例首次或第二次接受类固醇、新山地明（CsA）和米芙（每天两次，每次720毫克）治疗的初发肾移植受者。在第7、90和180天测定两种药物的PK（C0、C2和AUC(0 - 12h)）。在第7天和180天测试钙调神经磷酸酶活性、白细胞介素-2和干扰素-γ合成以及%CEM。通过C2监测调整CsA剂量。收集的数据包括：前6个月的BPAR以及6个月方案活检中的班夫组织学参数。
22例患者中有18例在治疗期间完成了1年的随访。6个月时的BPAR为18%（4/22）。14例受者中有50%的6个月方案活检显示有慢性移植肾肾病1。在第7天，CsA的C2和AUC中位数分别为138 ng/mL和6377 ng·h/mL，而MPA的C0为1.0 μg/mL，AUC = 23.9 μg·h/mL。3个月和6个月时CsA的C2中位数分别为1468和1720 ng/mL。MPA-AUC在3个月时达到治疗目标（32.3 μg·h/mL），6个月时为48.3 μg·h/mL。与无BPAR的患者相比，发生BPAR的患者显示CsA的AUC较低（P = 0.06），钙调神经磷酸酶活性的基线抑制明显较低（P < 0.005）。6个月方案活检中系膜基质的增加与较高的CsA C2相关（P = 0.01）。与标准人群相比，所有评估的生物标志物均受到显著抑制。
当米芙与CsA联合使用时，建议开始时使用较高剂量（720毫克×3天）以达到适当的PK目标并提高BPAR发生率。为预防慢性移植肾肾病，应从3个月起将CsA C2的目标值降低。
