Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Ann Pharmacother. 2010 Jan;44(1):19-27. doi: 10.1345/aph.1M511. Epub 2009 Dec 8.
Mycophenolate mofetil is widely used in islet transplant recipients and its active metabolite, mycophenolic acid (MPA), exhibits wide pharmacokinetic variability. However, to our knowledge, no limited sampling strategy (LSS) exists for monitoring MPA in this subpopulation.
To define optimal LSSs for MPA monitoring and to test their predictive performance in islet transplant recipients.
After written informed consent was obtained and upon administration of a steady-state morning mycophenolate mofetil dose, blood samples were collected at 0, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours from 16 stable islet transplant recipients. MPA concentrations were measured by a validated high-performance liquid chromatography method with ultraviolet detection and pharmacokinetic parameters analyzed by noncompartmental modeling. All 16 patients' profiles were used to develop the LSSs via multiple regression analysis. Potential LSSs were restricted to ones having R(2) 0.90 or greater and 3 or fewer time points within the first 4 hours postdose. Resulting equations were validated for their predictive performance using the jackknife method, with acceptable criteria for bias and precision preset to within +/-15%. In addition, 14 published LSSs (in the renal transplant population) were tested in our islet transplant patients.
Five LSSs met preset criteria and had conventional sampling times: AUC = 1.783 + 1.248C1 + 0.888C2 + 8.027C4 (R2 = 0.98, bias = -3.09%, precision = 9.53%) AUC = 2.778 + 1.413C1 + 0.963C3 + 7.511C4 (R2 = 0.97, bias = -3.22%, precision = 11.02%) AUC = 1.448 + 1.239C1 + 0.271C1.5 + 9.108 C4 (R2 = 0.96, bias = -1.90%, precision = 11.46) AUC = 1.410 - 0.259C0 + 1.443C1 + 9.622C4 (R2 = 0.96, bias = -2.68%, precision = 11.53%) AUC = 1.547 + 1.417C1 + 9.448C4 (R2 = 0.96, bias = -2.46%, precision = 11.14%) where AUC = area under the concentration-time curve. None of the other published LSSs in the renal transplant population met the preset criteria for bias and precision.
To our knowledge, these are the first precise and accurate LSSs for predicting MPA AUC developed specifically for islet transplant recipients. The LSS that we recommend is the one utilizing 2 concentrations: AUC = 1.547 + 1.417C1 + 9.448C4. This equation is convenient and clinically feasible. Other islet transplant centers may wish to validate our equation in their population or use our template as a guide to develop accurate and precise LSSs specific to their patient population.
霉酚酸酯在胰岛移植受者中广泛应用，其活性代谢产物霉酚酸（MPA）表现出广泛的药代动力学变异性。然而，据我们所知，在这个亚群中，并没有针对 MPA 监测的有限采样策略（LSS）。
确定用于监测 MPA 的最佳 LSS，并在胰岛移植受者中测试其预测性能。
在获得书面知情同意书并给予稳定状态的早晨霉酚酸酯莫夫剂量后，从 16 名稳定的胰岛移植受者中采集 0、0.3、0.6、1、1.5、2、3、4、6、8、10 和 12 小时的血样。采用经验证的高效液相色谱法（HPLC）结合紫外检测法测定 MPA 浓度，并采用非房室模型分析药代动力学参数。通过多元回归分析，使用所有 16 名患者的图谱来开发 LSS。潜在的 LSS 限制在 R（2）为 0.90 或更高，并且在给药后 4 小时内有 3 个或更少的时间点。使用刀切法对所得方程进行验证，预设偏差和精度的可接受标准为 +/-15%。此外，还测试了 14 种已发表的 LSS（在肾移植人群中）在我们的胰岛移植患者中的预测性能。
有 5 种 LSS 满足预设的偏差和精度标准，且具有常规采样时间：AUC=1.783+1.248C1+0.888C2+8.027C4（R2=0.98，偏差=-3.09%，精度=9.53%），AUC=2.778+1.413C1+0.963C3+7.511C4（R2=0.97，偏差=-3.22%，精度=11.02%），AUC=1.448+1.239C1+0.271C1.5+9.108C4（R2=0.96，偏差=-1.90%，精度=11.46%），AUC=1.410-0.259C0+1.443C1+9.622C4（R2=0.96，偏差=-2.68%，精度=11.53%），AUC=1.547+1.417C1+9.448C4（R2=0.96，偏差=-2.46%，精度=11.14%），其中 AUC 为浓度-时间曲线下面积。在肾移植人群中，其他已发表的 LSS 均不符合我们预设的偏差和精度标准。
据我们所知，这些是专门为胰岛移植受者开发的用于预测 MPA AUC 的首批精确和准确的 LSS。我们推荐的 LSS 是利用 2 种浓度的公式：AUC=1.547+1.417C1+9.448C4。该方程方便且在临床上可行。其他胰岛移植中心可能希望在其人群中验证我们的方程，或使用我们的模板作为指南，为其患者群体开发准确和精确的 LSS。
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