van Mourik I D, Thomson M, Kelly D A
Liver Unit, Birmingham Children's Hospital, Birmingham, England.
Liver Transpl Surg. 1999 Mar;5(2):107-11. doi: 10.1002/lt.500050203.
Cyclosporine (Sandimmune; Novartis Pharmaceuticals UK Ltd) is an effective immunosuppressive drug, but its lipid formulation and variable absorption may expose children to the risk of rejection during episodes of gastroenteritis after liver transplantation. Neoral (Novartis) is a microemulsified form of cyclosporine that may be better absorbed. In this study, the pharmacokinetic profiles of Neoral and Sandimmune were compared in stable children after liver transplantation to evaluate whether Neoral is more predictably absorbed. Eight children, 6 boys and 2 girls, with a mean age of 4.5 years (range, 1.2-12) were studied between 4 and 12 months after liver transplantation. Pharmacokinetic profiles were performed on each child by using the same dose (mg/kg) of Neoral or Sandimmune. Tmax, Cmax, Ctrough, and the area under the curve (AUC) were calculated and side effects were documented in children taking either drug for more than 3 months. Mean peak cyclosporine levels were higher and were achieved significantly sooner with Neoral (Cmax 790.5 +/- 216.5 ng/mL, P =.06; Tmax 1.8 +/- 1.0 hr, P =.01) than with Sandimmune (Cmax 589.4 +/- 313 ng/mL, Tmax 2.5 +/- 1.7 hr), implying more rapid and better absorption. There was no significant difference in overall drug exposure (AUC) and 12-hour trough levels between the two formulations (P >.05). Children with Roux-en-Y loop biliary anastomosis taking Neoral, however, showed greater increases in AUC (mean increase = 37%) than those with duct-to-duct anastomosis (mean increase = 16%). There was no correlation between 12-hour trough level and AUC for either Neoral (r2 = 0.48) or Sandimmune (r2 = -0.08); however, for both drugs, AUC correlated very well with the 2-hour post-dose level (r2 = 0.68 and 0.7, respectively). Hirsutism was reported in 4 of 6 children on Neoral and may be associated with higher peak levels. Neoral is more consistently absorbed than Sandimmune in children after liver transplantation and may be more effective prophylaxis against rejection. Because of the increased peak levels and drug exposure, which may influence side effects, particularly in children with Sandimmune malabsorption, we recommend a 1:0.75 dose conversion ratio in patients being converted from Sandimmune to Neoral.
环孢素（山地明；诺华制药英国有限公司）是一种有效的免疫抑制药物，但其脂溶性制剂和吸收的变异性可能使儿童在肝移植后发生胃肠炎期间面临排斥反应的风险。新山地明（诺华）是环孢素的微乳剂形式，可能具有更好的吸收性。在本研究中，对肝移植后病情稳定的儿童比较了新山地明和山地明的药代动力学特征，以评估新山地明的吸收是否更具可预测性。研究了8名儿童，6名男孩和2名女孩，平均年龄4.5岁（范围1.2 - 12岁），在肝移植后4至12个月进行研究。通过给予相同剂量（mg/kg）的新山地明或山地明对每个儿童进行药代动力学分析。计算了达峰时间（Tmax）、峰浓度（Cmax）、谷浓度（Ctrough）和曲线下面积（AUC），并记录了服用任一药物超过3个月的儿童的副作用。新山地明的平均环孢素峰浓度更高且达到时间显著更早（Cmax 790.5±216.5 ng/mL，P = 0.06；Tmax 1.8±1.0小时，P = 0.01），而山地明为（Cmax 589.4±313 ng/mL，Tmax 2.5±1.7小时），这意味着吸收更快且更好。两种制剂之间的总体药物暴露量（AUC）和12小时谷浓度无显著差异（P＞0.05）。然而，行Roux - en - Y袢式胆肠吻合术的儿童服用新山地明时，AUC的增加幅度（平均增加 = 37%）大于行胆管对胆管吻合术的儿童（平均增加 = 16%）。新山地明或山地明的12小时谷浓度与AUC之间均无相关性（r2分别为0.48和 - 0.08）；然而，对于两种药物，AUC与给药后2小时的血药浓度相关性都很好（r2分别为0.68和0.7）。6名服用新山地明的儿童中有4名报告有多毛症，可能与较高的峰浓度有关。肝移植后的儿童中，新山地明比山地明的吸收更稳定，可能对预防排斥反应更有效。由于峰浓度和药物暴露增加可能影响副作用，特别是对于存在山地明吸收不良的儿童，我们建议从山地明转换为新山地明的患者采用1:0.75的剂量转换率。
