Einsele Hermann, Reusser Pierre, Bornhäuser Martin, Kalhs Peter, Ehninger Gerhard, Hebart Holger, Chalandon Yves, Kröger Nicolaus, Hertenstein Bernd, Rohde Frank
University of Würzburg, Department of Internal Medicine II, Klinikstr. 6-8, 97070 Würzburg, Germany.
Blood. 2006 Apr 1;107(7):3002-8. doi: 10.1182/blood-2005-09-3786. Epub 2005 Dec 13.
Cytomegalovirus (CMV) infection is a major complication after allogeneic stem cell transplantation (SCT). Valganciclovir (V-GCV) is an oral prodrug hydrolyzed to the anti-CMV drug ganciclovir (GCV). A randomized, multicenter, crossover, open-label clinical trial compared exposure to GCV after V-GCV and intravenous GCV (IV-GCV) as preemptive therapy for CMV disease in SCT. The primary objective was to compare exposure to GCV in patients with CMV infection stratified for intestinal graft-versus-host disease (I-GVHD). Secondary objectives were the assessment of safety and efficacy. Patients without I-GVHD had a higher exposure to GCV after V-GCV when compared with IV-GCV (area under the concentration-time curve from drug administration to last observed concentration after 12 hours [AUC(0-12)] 53.8 +/- 17.97 microg/mL . h [mean +/- SD] vs 39.5 +/- 13.91; P < .001; ratio of V-GCV/IV-GCV was 1.4; 90% confidence interval [CI], 1.2-1.5). This was also true in patients with I-GVHD grades I-II (AUC(0-12) 52.9 +/- 21.75 vs 33.1 +/- 12.97 mug/mL . h; P = .018; ratio 1.6; 90% CI, 1.3-2.0). Absolute bioavailability of GCV after V-GCV was approximately 75% in individuals with or without I-GVHD grades I-II. No severe GCV-related toxicity was observed and efficacy and safety was comparable (84-day follow-up). This supports the use of V-GCV in SCT, even in patients with I-GVHD grades I-II. Due to higher exposure after V-GCV compared with IV-GCV, patients should be monitored carefully for safety reasons.
巨细胞病毒（CMV）感染是异基因干细胞移植（SCT）后的主要并发症。缬更昔洛韦（V-GCV）是一种口服前体药物，可水解为抗CMV药物更昔洛韦（GCV）。一项随机、多中心、交叉、开放标签的临床试验比较了V-GCV和静脉注射更昔洛韦（IV-GCV）作为SCT中CMV疾病抢先治疗后GCV的暴露情况。主要目标是比较CMV感染且分层为肠道移植物抗宿主病（I-GVHD）的患者中GCV的暴露情况。次要目标是评估安全性和有效性。与IV-GCV相比，无I-GVHD的患者在接受V-GCV治疗后GCV暴露更高（给药至12小时后最后观察浓度的浓度-时间曲线下面积[AUC(0-12)]为53.8±17.97μg/mL·h[平均值±标准差]，而IV-GCV为39.5±13.91；P<.001；V-GCV/IV-GCV的比值为1.4；90%置信区间[CI]为1.2-1.5）。I-II级I-GVHD患者也是如此（AUC(0-12)为52.9±21.75 vs 33.1±12.97μg/mL·h；P=.018；比值为1.6；90%CI为1.3-2.0）。无论有无I-II级I-GVHD，V-GCV后GCV的绝对生物利用度约为75%。未观察到严重的GCV相关毒性，且疗效和安全性相当（84天随访）。这支持在SCT中使用V-GCV，即使是I-II级I-GVHD患者。由于与IV-GCV相比，V-GCV后暴露更高，出于安全原因，应对患者进行密切监测。
