The University of Queensland, Faculty of Health Sciences, Brisbane, QLD 4072, Australia.
Transplant Rev (Orlando). 2011 Apr;25(2):47-57. doi: 10.1016/j.trre.2010.06.001. Epub 2010 Dec 28.
This article summarizes part of a consensus meeting about mycophenolate (MPA) therapeutic drug monitoring held in Rome under the auspices of The Transplantation Society in November 2008 (Clin J Am Soc Nephrol. 2010;5:341-358). This part of the meeting focused on the clinical pharmacokinetics of MPA and included discussion on how to measure MPA (active drug) exposure and the differences between the currently available formulations.
Because of variability in the dose-concentration relationship, MPA exposure should be measured and doses should be adjusted accordingly to achieve optimal clinical outcomes. Suggested therapeutic exposures derived for MPA from mycophenolate mofetil (MMF) may differ to those that could be useful for MPA from enteric-coated mycophenolate sodium (EC-MPS), particularly if limited sampling strategies or single concentration, especially trough concentrations, is used, as the concentration-time profiles of MPA from the 2 formulations are quite different. The 2 MPA formulations cannot be considered as bioequivalent. The area under the concentration-time curve (AUC 0-12) is considered the criterion standard for monitoring of MPA, which is a reflection of exposure to the drug over the entire dosing period. If a limited sampling protocol coupled with multilinear regression or Bayesian estimation is used to estimate this parameter, it should be used only for the population in which the model has been developed and should preferably include at least one time point after 4 hours (preferably around 8 or 9 hours after MMF dosing). If a single time point is to be used as a surrogate for an AUC 0-12, trough concentration of MPA may be the most practical but, from a pharmacokinetic standpoint, is not the most informative time point to choose. Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC 0-12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC 0-12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. Lower (or higher) than expected total MPA exposure in patients with severe renal impairment may still indicate sufficient free MPA exposure. Mycophenolate free exposure measurement/estimation is likely to be beneficial in patients with severe renal impairment (creatinine clearance b25 mL/min) to guide dosage estimation, especially because renal function changes over time after transplant, while recognizing that robust prospective studies to show the clinical advantage of measuring free MPA exposure are still required. Lower total measured MPA exposure in patients with hypoalbuminemia may still indicate sufficient free MPA exposure. Mycophenolate free concentration measurement and estimation of exposure are likely to be beneficial in patients with a serum albumin less than or equal to 31 g/L to guide interpretation of MPA exposure. A 1.5-g twice-daily starting dose of MMF rather than a 1-g twice-daily starting dose of MMF is more likely to achieve the minimum target MPA exposure in adult transplant recipients receiving concomitant cyclosporine therapy. Because the cyclosporine dose is progressively tapered following transplantation, MPA exposure should be measured repeatedly and MMF should be doses adjusted accordingly to achieve optimal clinical outcome. Mycophenolate exposure should be measured in the first week after transplant, then each week for the first month, each month until month 3, and subsequently every 3 months up to 1 year with appropriate dosage adjustment, as AUC is likely to increase over time. After 1 year, if dosage requirement has stabilized, MPA exposure can be assessed each time the immunosuppressive regimen is changed or a potentially interacting drug is introduced or withdrawn. Assessment of UGT1A9 single nucleotide polymorphisms (-275TNA, -2152CNT, -440CNT, -331TNC) should be considered before transplantation to assist in dosing decisions to achieve optimal MPA exposure immediately after transplant. Consideration of the points summarized above should lead to more effective dosage adjustment based on sound applied pharmacokinetic and pharmacodynamic principles.
本文总结了 2008 年 11 月在罗马举行的移植学会（The Transplantation Society）主持的关于霉酚酸（MPA）治疗药物监测的共识会议的一部分内容（Clin J Am Soc Nephrol. 2010;5:341-358）。会议的这一部分重点讨论了 MPA 的临床药代动力学，包括如何测量 MPA（活性药物）暴露以及当前可用制剂之间的差异。
由于剂量-浓度关系的变异性，应测量 MPA 暴露并相应调整剂量以达到最佳临床结果。从霉酚酸酯（MMF）推导得出的 MPA 治疗暴露量可能与从肠衣型吗替麦考酚酯钠（EC-MPS）获得的 MPA 有用的暴露量不同，特别是如果使用有限的采样策略或单一浓度，特别是谷浓度时，因为这两种制剂的 MPA 浓度-时间曲线非常不同。这两种 MPA 制剂不能被认为是生物等效的。曲线下面积（AUC 0-12）被认为是监测 MPA 的标准，它反映了整个给药期间药物的暴露情况。如果使用有限的采样方案结合多线性回归或贝叶斯估计来估计该参数，则应仅用于已开发模型的人群，并且最好包括 MMF 给药后 4 小时后（最好在 8 或 9 小时左右）的至少一个时间点。如果要使用单点作为 AUC 0-12 的替代值，则 MPA 的谷浓度可能是最实用的，但从药代动力学的角度来看，选择最有意义的时间点并不是。由于尚未很好地开发和全面评估用于估计 EC-MPS 中 MPA 暴露的有限采样策略，也没有报告准确的贝叶斯估计值，因此仍需要测量 AUC 0-12 以获得接受 EC-MPS 治疗的患者中 MPA 暴露的可靠估计值。测量 MPA 谷浓度不应用于评估 EC-MPS 给药后 MPA 的暴露情况。由于尚未很好地开发和全面评估用于估计 EC-MPS 中 MPA 暴露的有限采样策略，也没有报告准确的贝叶斯估计值，因此仍需要测量 AUC 0-12 以获得接受 EC-MPS 治疗的患者中 MPA 暴露的可靠估计值。测量 MPA 谷浓度不应用于评估 EC-MPS 给药后 MPA 的暴露情况。严重肾功能不全患者的总 MPA 暴露低于（或高于）预期，仍可能表明游离 MPA 暴露充足。在严重肾功能不全（肌酐清除率 b25 mL/min）的患者中，测量/估计霉酚酸游离暴露量可能是有益的，特别是因为移植后肾功能随时间变化，同时认识到仍需要进行稳健的前瞻性研究以显示测量游离 MPA 暴露的临床优势。血清白蛋白水平低于或等于 31 g/L 的患者的总 MPA 暴露量较低，但仍可能表明游离 MPA 暴露充足。在血清白蛋白水平小于或等于 31 g/L 的患者中，测量霉酚酸游离浓度和估计暴露量可能是有益的，以指导 MPA 暴露的解释。与每天两次给予 1 克 MMF 相比，每天两次给予 1.5 克 MMF 更有可能使接受环孢素治疗的成年移植受者达到最低目标 MPA 暴露量。由于环孢素剂量在移植后逐渐减少，因此应反复测量 MPA 暴露量并相应调整 MMF 剂量以达到最佳临床结果。应在移植后第一周测量霉酚酸暴露量，然后在第一个月的每周测量一次，每月测量一次直至第三个月，然后每 3 个月测量一次，直至 1 年，同时进行适当的剂量调整，因为 AUC 可能会随时间增加。1 年后，如果剂量要求稳定，则可以在每次改变免疫抑制方案或引入或撤回潜在相互作用的药物时评估 MPA 暴露情况。应在移植前考虑 UGT1A9 单核苷酸多态性（-275TNA、-2152CNT、-440CNT、-331TNC），以协助在移植后立即实现最佳 MPA 暴露量的剂量决策。考虑到上述要点应导致根据合理的应用药代动力学和药效学原则进行更有效的剂量调整。
