Current target ranges of mycophenolic acid exposure and drug-related adverse events: A 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients
Current target ranges of mycophenolic acid exposure and drug-related adverse events: A 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients
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DOI：
10.1016/j.clinthera.2008.04.014
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发表时间：
2008-04-01
影响因子：
3.2
通讯作者：
Vanrenterghem, Yves
中科院分区：
文献类型：
--
作者：
Kuypers, Dirk R. J.;de Jonge, Hylke;Vanrenterghem, Yves
背景资料：最近的两项随机临床试验-固定剂量与浓度控制和Apomygre-evaluating治疗药物监测的好处吗替麦考酚酯（MMF）在肾移植受者报告了相互矛盾的结果。在这两项研究中，目标霉酚酸（MPA）AUC（0 - 12 h）范围（即，用于指导MMF给药的值）来自既往研究，该研究确定了30 - 60 mg/L环孢菌素治疗患者的目标MPA AUC（0 - 12 h）范围。h（-1）。两项研究都发现MPA暴露与急性排斥反应之间存在关联。然而，只有一项研究发现，与固定剂量相比，浓度控制的MMF剂量与活检证实的急性排斥反应事件较少显著相关。没有降低发生率的MMF相关的不良事件（AE），观察到在任何2个试验时，MMF浓度控制和固定dose.Objective：本研究的目的是评估的临床效用的目标MPA AUC（0 - 12小时）范围在30和60 mg/L之间。h（-1）将移植后不同时间窗内的药物暴露与AE相关联，从而识别出MMF相关AE风险增加的患者。尿苷葡萄糖醛酸基转移酶1A9（UGT 1A9）和MRP 2基因单核苷酸多态性（SNP）的影响（即，编码UGT 1A9和多药耐药蛋白转运蛋白MRP 2）-均参与MPA代谢-通过应用当前建议的目标MPA AUC（0 - 12 h）范围评估分层MPA暴露。方法：我们在肾移植受者中进行了一项为期5年的临床随访研究，在移植后7天、6周、3个月、1年、3年和5年使用简化的AUC测量来测量MPA暴露。根据临床适应症（例如，持续性白细胞减少症、慢性无热性腹泻、肾移植物BK-多瘤病毒感染）调整MMF剂量。结果：100例白色原发性肾移植受者（59例男性，41例女性;平均[SD]年龄51.4 [13.8]岁）被纳入本研究。98例患者接受了来自已故供体的肾移植。MPA AUC（0 - 12 h）范围> 60 mg/L时，白细胞减少症发作次数明显增多。h（-1）（P = 0.03）。贫血也与较高的MPA暴露范围显著相关（MPA AUC（0 - 12 h）范围<30、30 - 60和> 60 mg/L时，贫血发生率分别为40.8%、52.2%和64.3%）。h（-1）; P = 0.004）。在白细胞减少症之前或之后的时间窗内，平均MPA AUC（0 - 12 h）显著较高（平均值[SD] 59.7 [31.0] vs 46.5 [26.0] mg/L）。h（-1）; P = 0.004）和贫血（平均[SD]血红蛋白<12 g/L。d（-1）：52.5 [30.0] vs 42.2 [21.2] mg/L。h（-1），P = 0.002;血红蛋白<10 g/L d（-1）：56.2 [32.5] vs 45.6 [24.7] mg/L。h（-1），P = 0.005）。未发现腹泻或感染事件与目标MPA AUC（0 - 12 h）范围之间存在关联。在携带UGT 1A9 T-275 A和/或C-2152 T SNP的受体中，MPA AUC（0 - 12 h）测量值在低MPA暴露范围内的比例显著较高（MPA AUC（0 - 12 h）范围<30、30 - 60和> 60 mg/L分别为23.7%、16.6%和12.6%）。h（-1）;结论：患有与MMF相关的白细胞减少症或贫血的肾移植受者可能至少部分受益于基于目标治疗MPA AUC（0 - 12 h）范围为30 - 60 mg/L的MMF剂量调整。h（-1）。本研究未发现这些目标MPA AUC（0 - 12 h）范围在指导胃肠道或感染性AE患者的MMF给药方面具有临床实用性。有必要进行更大规模的前瞻性研究，以检查携带UGTIA9 T-275A和/或C-2152T SNP的患者中MPA表达不足的风险。
Background: Two recent randomized clinical trials-Fixed Dose Versus Concentration Controlled and the Apomygre-evaluating the benefit of therapeutic drug monitoring of mycophenolate mofetil (MMF) in renal allograft recipients reported conflicting results. In both studies, target mycophenolic acid (MPA) AUC(0-12h) ranges (le, values used to guide MMF dosing) were derived from a previous study establishing target MPA AUC(0-12h) ranges in cyclosporine-treated patients between 30 and 60 mg/L . h(-1). Both studies found an association between MPA exposure and acute rejection. However, only one of the studies found concentration-controlled MMF dosing to be significantly associated with less biopsy-proven acute-rejection episodes compared with fixed dosing. No reduced incidence of MMF-related adverse events (AEs) was observed in either of the 2 trials when MMF concentration-controlled and fixed dosing were compared.Objective: The aim of this study was to assess the clinical utility of target MPA AUC(0-12h) ranges between 30 and 60 mg/L . h(-1) in associating drug exposure with AEs within different time windows after transplantation, thereby identifying patients at increased risk for MMF-related AEs. The effects of single nucleotide polymorphisms (SNPs) of the uridine glucuronosyltransferase 1A9 (UGT1A9) and MRP2 genes (ie, coding for the UGT1A9 and the multidrug resistance protein transporter MRP2)-both involved in MPA metabolism-on stratified MPA exposure were assessed by applying the current advised target MPA AUC(0-12h) ranges.Methods: We conducted a 5-year clinical follow-up study in renal allograft recipients in whom MPA exposure was measured at 7 days, 6 weeks, 3 months, 1, 3, and 5 years posttransplantation using abbreviated AUC measurements. MMF dose adjustments were based on clinical indications (eg, persistent leukopenia, chronic afebrile diarrhea, BK-polyomavirus infection of the renal allograft). Clinicians were blinded to the results of the AUC measurements.Results: One hundred white de novo renal allograft recipients (59 men, 41 women; mean [SD] age 51.4 [13.8] years) were included in this study. Ninety-eight patients received a renal allograft from a deceased donor. Significantly more episodes of leukopenia were associated with MPA AUC(0-12h) ranges > 60 mg/L . h(-1) (P = 0.03). Anemia was also significantly associated with higher MPA exposure ranges (incidence of anemia was 40.8%, 52.2%, and 64.3% for MPA AUC(0-12h) ranges < 30, 30-60, and > 60 mg/L . h(-1), respectively; P = 0.004). Mean MPA AUC(0-12h) was significantly higher in the time window immediately preceding or following leukopenia (mean [SD] 59.7 [31.0] vs 46.5 [26.0] mg/L . h(-1); P = 0.004) and anemia (mean [SD] hemoglobin < 12 g/L . d(-1): 52.5 [30.0] vs 42.2 [21.2] mg/L . h(-1), P = 0.002; hemoglobin < 10 g/L d(-1): 56.2 [32.5] vs 45.6 [24.7] mg/L . h(-1), P = 0.005). No association was found between incident episodes diarrhea or infection and target MPA AUC(0-12h) ranges. A significantly higher proportion of MPA AUC(0-12h) measurements in recipients carrying the UGT1A9 T-275A and/or C-2152T SNP were in the low MPA exposure range (23.7%, 16.6%, and 12.6% for MPA AUC(0-12h) ranges < 30, 30-60, and > 60 mg/L . h(-1), respectively; P = 0.02).Conclusions: Renal allograft recipients suffering from leukopenia or anemia related to MMF could potentially benefit, at least in part, from MMF dose adjustments based on target therapeutic MPA AUC(0-12h) ranges between 30 and 60 mg/L . h(-1). This study did not find these target MPA AUC(0-12h) ranges to be of clinical utility in guiding MMF dosing in patients with gastrointestinal or infectious AEs. Larger prospective studies are necessary to examine the risk for MPA underexposure in patients carrying the UGTIA9 T-275A and/or C-2152T SNP.