Windreich Randy M, Goyal Rakesh K, Joshi Rujuta, Kenkre Tanya S, Howrie Denise, Venkataramanan Raman
Division of Blood and Marrow Transplantation and Cellular Therapies, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pennsylvania.
Division of Blood and Marrow Transplantation and Cellular Therapies, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pennsylvania.
Biol Blood Marrow Transplant. 2016 Apr;22(4):682-689. doi: 10.1016/j.bbmt.2015.12.013. Epub 2015 Dec 29.
Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose-escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC(0-24) of 40 to 80 μg·hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 μg/mL. During the CI schedule, MPA AUC(0-24) was maintained at a mean of 40.1 μg·hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 μg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in pediatric HCT recipients compared with stable pediatric renal transplant patients or adult transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation.
霉酚酸酯（MMF）是霉酚酸（MPA）的酯前体药物，越来越多地用于预防移植物抗宿主病（GVHD）。在儿科造血细胞移植（HCT）受者中，经验性的固定剂量递增策略未能达到目标MPA暴露水平。我们评估了一种基于药代动力学的给药方法的安全性和可行性，该方法在儿科HCT受者中使用新型的连续输注（CI）方式给予MMF。所有患者均接受环孢素A和MMF进行清髓预处理以预防GVHD。MMF于第0天开始，剂量为每8小时15mg/kg。根据稳态药代动力学，将MMF转换为CI，以使MPA的总AUC(0-24)达到40至80μg·小时/mL。调整MMF剂量以维持MPA的总稳态浓度（Css）在1.7至3.3μg/mL。在CI给药期间，MPA的AUC(0-24)平均维持在40.1μg·小时/mL（范围为20.6至63.8），19例患者中有17例（89%）的MPA Css达到了1.7至3.3μg/mL的目标范围。19例患者中有18例（95%）在移植后中位数13天（范围为8至41天）实现中性粒细胞植入，在移植后39天（范围为17至298天）实现血小板植入。18例可评估患者中有6例（33%）发生了II至IV期急性GVHD，15例中有2例（13%）发生了慢性GVHD。9例患者因胃肠道症状（n = 6）、血细胞计数低（n = 4）和病毒感染（n = 3）而减少了MMF剂量。5例急性淋巴细胞白血病患者复发，其中4例死亡。19例患者中有15例存活，中位随访时间为2.4年（范围为0.4至4.9年），3年无事件生存率和总生存率分别为68%和79%。在这项关于药代动力学指导MMF给药的初步研究中，我们未观察到毒性死亡、良好的植入以及III至IV级急性和慢性GVHD的低发生率。我们发现，与稳定的儿科肾移植患者或成人移植患者相比，儿科HCT受者的半衰期显著更短，药物清除率更高。该方案值得在更大规模的接受清髓性移植的儿科患者队列中进一步验证。
