Faculty of Pharmacy and Pharmaceutical Sciences, Katz Group Centre for Pharmacy and Health Research, University of Alberta, Room 3-142D, 11361-87 Ave, Edmonton, AB, T6G 2E1, Canada.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
Clin Pharmacokinet. 2019 Dec;58(12):1533-1552. doi: 10.1007/s40262-019-00802-z.
Mycophenolic acid is commonly prescribed in adult kidney transplant recipients for preventing graft rejection. A therapeutic target for total mycophenolic acid area under the concentration-time curve (30-60 mg h/L) has been established in adult kidney transplant recipients and widely referenced today. However, this specific target range does not adequately characterize mycophenolic acid-associated adverse effects. The primary objective of this qualitative and critical review was to characterize the exposure-toxicity relationships of mycophenolic acid in an attempt to determine whether exposure thresholds can be identified. The secondary objective was to determine the associations of clinical variables with specific adverse effects. The inclusion criteria consisted of all peer-reviewed papers in adult kidney transplant subjects (average study age > 18 years) with both exposure (area under the concentration-time curve) and toxicity data. The exclusion criteria were papers involving the pediatric population, studies lacking either area under the concentration-time curve or toxicity data, or studies with no apparent reported variations in area under the concentration-time curves. Of the 28 papers identified, inconsistent findings have been reported for the most frequently characterized adverse events of mycophenolic acid (gastrointestinal, infectious, and hematological), while promising exposure thresholds (i.e., > 40-60 mg h/L for total mycophenolic acid) have been suggested by a few studies. The roles of free mycophenolic acid exposure, mycophenolic acid metabolites, or clinical factors influencing the manifestation of the toxicities also remain to be clarified. Although it is not yet possible to define toxicity threshold(s) for the purpose of mycophenolic acid therapeutic drug monitoring, the information obtained and the limitations identified in this comprehensive literature body have provided a good foundation for future investigations.
霉酚酸通常被开给成年肾移植受者，以预防移植物排斥反应。在成年肾移植受者中，已经建立了霉酚酸总浓度-时间曲线下面积（30-60mg·h/L）的治疗目标，并被广泛引用。然而，这个特定的目标范围并不能充分描述霉酚酸相关的不良反应。本定性和批判性综述的主要目的是描述霉酚酸的暴露-毒性关系，试图确定是否可以确定暴露阈值。次要目的是确定与特定不良反应相关的临床变量的关联。纳入标准包括所有涉及成年肾移植受者的同行评议论文（平均研究年龄＞18 岁），这些论文既有暴露（浓度-时间曲线下面积）数据，也有毒性数据。排除标准为涉及儿科人群的论文、缺乏浓度-时间曲线下面积或毒性数据的研究，或明显没有报告浓度-时间曲线下面积变化的研究。在确定的 28 篇论文中，霉酚酸最常描述的不良反应（胃肠道、感染和血液学）的报道结果不一致，而少数研究提出了有希望的暴露阈值（即总霉酚酸＞40-60mg·h/L）。游离霉酚酸暴露、霉酚酸代谢物或影响毒性表现的临床因素的作用仍有待阐明。虽然目前还不可能为霉酚酸治疗药物监测的目的定义毒性阈值，但从这个全面的文献综述中获得的信息和确定的局限性为未来的研究提供了良好的基础。
