Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus University Medical Center, Rotterdam, The Netherlands.
Ther Drug Monit. 2010 Oct;32(5):606-14. doi: 10.1097/FTD.0b013e3181efd715.
For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration-time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two-compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients.
十余年来，霉酚酸酯（MMF）一直被用作实体器官移植受者的免疫抑制剂，以预防移植物排斥。口服后，前药 MMF 迅速水解为活性代谢物霉酚酸（MPA）。MMF 在造血干细胞移植（HSCTx）和自身免疫性疾病（AID）中的应用越来越多。与肾移植受者（RTx）相比，MPA 在 HSCTx 患者中的清除率增加，在 AIDS 患者中降低。本研究的目的是描述 RTx、HSCTx 和 AID 患者中 MPA 的清除率，并检验清除率的差异是否可以用临床化学参数来描述。对 19 例合用环孢素的 RTx 患者、17 例合用他克莫司的 RTx 患者、38 例合用环孢素的 HSCTx 患者和 36 例 AID 患者的 MPA 浓度-时间曲线进行了回顾性非线性混合效应模型（一阶条件估计）分析。测试了以下协变量：MMF 治疗的适应证、性别、年龄、体重、血浆白蛋白、环孢素合用、剂量和预剂量血药浓度、肌酐清除率和血红蛋白。MPA 的药代动力学用具有时间滞后的一阶吸收的两室模型描述。单变量分析显示，MPA 清除率与血浆白蛋白、环孢素剂量和预剂量血药浓度、肌酐清除率、血红蛋白和 MMF 治疗适应证（RTx、HSCTx 或 AID）相关（P < 0.001）。所有显著的协变量都被组合在一个中间多变量模型中，然后进行向后消除。在不影响拟合的情况下，可以将 MMF 治疗的适应证从中间模型中删除。清除率与环孢素预剂量浓度和血浆白蛋白之间的相关性在最终模型中仍然显著，并能描述 MMF 治疗不同适应证之间清除率的差异。RTx、HSCTx 和 AID 患者的清除中位数分别为 30.2、45.6 和 10.7 L/h。结论：血浆白蛋白浓度和环孢素预剂量浓度能够描述 RTx、HSCTx 和 AID 患者之间 MPA 清除率的差异。
