Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
Biol Blood Marrow Transplant. 2010 Mar;16(3):421-9. doi: 10.1016/j.bbmt.2009.11.010.
There are limited data as to the effectiveness of mycophenolate mofetil (MMF) plus high-dose corticosteroids for the treatment of acute graft-versus-host disease (aGVHD), and even less data regarding the pharmacokinetic disposition and exposure-response relationship of MMF in individuals with GVHD. MMF pharmacokinetics were studied in a multicenter Blood and Marrow Transplant Clinical Trials Network randomized phase II trial evaluating the effectiveness of MMF as one of 4 agents added to corticosteroids as treatment of aGVHD. Thirty-two of the patients randomized to receive MMF underwent pharmacokinetic sampling in weeks 1 and 2 were studied. Mean age was 41 +/- 13.6 years. Twenty one (65.6%), 5 (15.6%), 6 (18.8%) patients had a complete response (CR), partial response (PR) or lesser response by day 28, respectively. Twenty-five (78.1%), 2 (6.3%), 5 (15.6%) patients had a CR, PR, or other response by day 56 to treatment, respectively. Mycophenolic acid (MPA) pharmacokinetic measurements from weeks 1 and 2 did not correlate with CR at either day 28 or day 56 (P > .07); however, if the mean of weeks 1 and 2 total MPA troughs was >0.5 microg/mL or that of an unbound trough was >0.015 microg/mL, then a significantly greater proportion achieved CR + PR at days 28 and 56. CR + PR at day 28 was observed in 19 of 19 patients (100%) with a mean total trough >0.5 mg/mL, but in only 7 of 13 (54%) with a mean total trough < or =0.5 microg/mL (P = .002). Similarly, CR + PR at day 28 was seen in 15 of 15 patients (100%) with an unbound trough concentration >0.015 microg/mL, but in only 11 of 17 (65%) with an unbound trough concentration < or =0.015 microg/mL (P = .02). There was no association between the pharmacokinetic measures and risk of infection by day 90 or overall survival (OS) at day 180 postrandomization. About one-half of subjects did not achieve the favorable MPA total and unbound trough concentrations. The current practice of MMF 1 gm twice daily dosing provides low plasma concentrations in many patients. Higher doses may improve the efficacy of MMF as aGVHD therapy.
关于霉酚酸酯（MMF）联合大剂量皮质类固醇治疗急性移植物抗宿主病（aGVHD）的疗效，数据有限，而关于 MMF 在患有 GVHD 的个体中的药代动力学分布和暴露-反应关系的数据则更少。在一项多中心血液和骨髓移植临床试验网络随机 II 期试验中，评估了 MMF 作为皮质类固醇治疗 aGVHD 的 4 种附加药物之一的有效性，对 MMF 的药代动力学进行了研究。在接受 MMF 治疗的 32 例随机分组患者中，在第 1 周和第 2 周进行了药代动力学采样。平均年龄为 41 ± 13.6 岁。第 28 天分别有 21 例（65.6%）、5 例（15.6%）和 6 例（18.8%）患者完全缓解（CR）、部分缓解（PR）或缓解程度较轻。第 28 天分别有 25 例（78.1%）、2 例（6.3%）和 5 例（15.6%）患者获得 CR、PR 或其他治疗反应。第 1 周和第 2 周的霉酚酸（MPA）药代动力学测量值与第 28 天或第 56 天的 CR 均无相关性（P >.07）；然而，如果第 1 周和第 2 周的平均总 MPA 谷浓度>0.5 μg/mL 或游离 MPA 谷浓度>0.015 μg/mL，则在第 28 天和第 56 天有更大比例的患者获得 CR+PR。第 28 天观察到 19 例（100%）患者的 CR+PR，这些患者的平均总谷浓度>0.5 μg/mL，但在平均总谷浓度≤0.5 μg/mL 的 13 例患者中仅观察到 7 例（54%）（P =.002）。同样，在游离 MPA 浓度>0.015 μg/mL 的 15 例患者中观察到第 28 天的 CR+PR，但在游离 MPA 浓度≤0.015 μg/mL 的 17 例患者中仅观察到 11 例（65%）（P =.02）。在第 90 天的感染风险或随机后第 180 天的总生存率（OS）方面，药代动力学指标与这些结果之间没有关联。大约一半的患者没有达到理想的 MPA 总浓度和游离浓度。目前 MMF 每日 2 次 1 克的剂量方案在许多患者中提供了较低的血浆浓度。较高的剂量可能会提高 MMF 作为治疗 aGVHD 的疗效。
