Jenke A, Renner U, Richte M, Freiberg-Richter J, Platzbecker U, Helwig A, Thiede H M, Schäfer-Eckart K, Ehninger G, Bornhäuser M
Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Städtisches Klinikum Nord, Med. Klinik V, Flurstrasse 17, 90 419 Nürnberg, Germany.
Clin Transplant. 2001 Jun;15(3):176-84. doi: 10.1034/j.1399-0012.2001.150306.x.
Mycophenolate mofetil (MMF) has shown synergistic effects in combination with cyclosporin A (CsA) in prevention of acute graft versus host disease (GvHD) after allogeneic blood stem cell transplantation (BSCT) in preclinical animal models. After having measured low plasma levels of the active metabolite mycophenolic acid (MPA) in recipients of allogeneic blood stem cell transplants after oral administration of MMF, we initiated a phase I/II study evaluating different dose levels of the intravenous (i.v.) formulation together with standard dose CsA.
A total of 15 patients received i.v. MMF in two split doses for 21 d after allogeneic BSCT from related (n=9) and unrelated (n=6) donors. Total daily doses of 25, 28, 31 and 34 mg/kg were investigated in 3-5 patients at each dose level. Plasma concentrations of MPA and its metabolite mycophenolic acid glucuronide (MPAG) were measured by high-performance liquid chromatography (HPLC).
Mean trough blood levels of MPA ranged between 68.8 and 340 ng/mL with a median of 146.7 ng/mL. The mean MPA AUC0-12 h after first dose ranged between 19349+/-5087 ng * h/mL and 25705+/-3042 ng * h/mL and correlated with the dose level of MMF. The incidence of acute GvHD>grade I was 40%. No dose limiting toxicities were observed.
The application of i.v. MMF is safe at a weight-adjusted dose between 25 and 34 mg/kg after allogeneic BSCT. The measured trough blood levels of MPA in patients after BSCT were ten times lower than in healthy volunteers. The toxicity induced by the conditioning therapy seems to negatively influence the pharmacokinetic behavior of MMF, MPA and MPAG.
在临床前动物模型中，霉酚酸酯（MMF）与环孢素A（CsA）联合应用于预防异基因造血干细胞移植（BSCT）后的急性移植物抗宿主病（GvHD）显示出协同效应。在口服MMF的异基因造血干细胞移植受者中检测到活性代谢物霉酚酸（MPA）的血浆水平较低后，我们启动了一项I/II期研究，评估不同剂量水平的静脉注射（i.v.）制剂与标准剂量CsA联合应用的情况。
15例患者在接受来自相关供者（n = 9）和无关供者（n = 6）的异基因BSCT后，分两次静脉注射MMF，共21天。每个剂量水平有3 - 5例患者接受每日总剂量为25、28、31和34 mg/kg的治疗。通过高效液相色谱法（HPLC）测定MPA及其代谢物霉酚酸葡萄糖醛酸苷（MPAG）的血浆浓度。
MPA的平均谷血浓度在68.8至340 ng/mL之间，中位数为146.7 ng/mL。首次给药后MPA的平均AUC0 - 12 h在19349±5087 ng·h/mL至25705±3042 ng·h/mL之间，并与MMF的剂量水平相关。急性移植物抗宿主病> I级的发生率为40%。未观察到剂量限制性毒性。
异基因造血干细胞移植后，静脉注射MMF在体重调整剂量为25至34 mg/kg时是安全的。造血干细胞移植患者中测得的MPA谷血浓度比健康志愿者低10倍。预处理方案诱导的毒性似乎对MMF、MPA和MPAG的药代动力学行为有负面影响。
