Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation
Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation
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DOI：
10.1038/sj.bmt.1705958
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发表时间：
2008-04-01
影响因子：
4.8
通讯作者：
Junghanss, C.
中科院分区：
文献类型：
--
作者：
Lange, S.;Mueller, S. C.;Junghanss, C.
吗替麦考酚酯 (MMF) 已成功用于实体器官移植 (SOT)，最近又用于非清髓性造血干细胞移植 (HSCT)，以预防移植物排斥和急性移植物抗宿主病。然而，与 SOT 相比，MMF 在 HSCT 中的药代动力学似乎有所不同。在这里，我们在非清髓性犬 HSCT 模型中分析了 MMF 的活性代谢物霉酚酸 (MPA) 的药代动力学。狗接受非清髓性 TBI 进行调理，然后进行白细胞抗原相同的同窝 HSCT 和含有环孢素 A (CsA) 和不同剂量 MMF 的免疫抑制剂。在第2、14和27天进行药代动力学。MMF的剂量从10 mg/kg增加到30 mg/kg倾向于使曲线下面积(AUC)和表观口服清除率分别增加45%和110%。施用剂量与 MPA 浓度或血谷水平没有线性关系。随着时间的推移，没有发生明显的药物蓄积。使用每日两次 MMF 方案，我们得出结论，在 HSCT 中无法达到 SOT 推荐的 30-60 μg/mlh AUC。毒性不允许单剂量高于 30 mg/kg。因此，如果需要更大的 AUC 以确保 HSCT 中足够的免疫抑制，MMF 可能必须每天至少给药 3 次。
Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation ( SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30-60 mu g/mlh as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.