ST LOUIS (MD Consult) - On May 28, 2009, Astellas announced that the US Food and Drug Administration (FDA) has approved the use of Prograf (tacrolimus) in conjunction with mycophenolate mofetil (MMF) for the prevention of organ rejection in kidney transplant recipients. Prograf was initially approved by the FDA in 1994 and is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants. The manufacturer states that 2007 figures provided by the United Network for Organ Sharing show that 79.3% of kidney transplant recipients were discharged from the hospital with a Prograf plus MMF medication regimen.

 
The FDA's approval of the Prograf and MMF combination for use in kidney transplant recipients was granted on the basis of a review of 2 clinical studies involving approximately 2,000 kidney transplant recipients. A phase 3, multicenter, open-label clinical trial was conducted in which 424 kidney transplant recipients received Prograf or cyclosporine (Cya) in combination with MMF, basiliximab induction, and corticosteroids (CS). Investigators reported that the rate for the combined end point of biopsy-proven acute rejection, graft failure, death, and/or lost to follow-up at 12 months in the Prograf/MMF group was similar to the rate in the Cya/MMF group. However, the mortality at 12 months in patients receiving Prograf/MMF was 4.2% compared with 2.4% in patients receiving CyA/MMF, including cases attributed to overimmunosuppression.

 

The other clinical trial reviewed as part of the drug approval process was a prospective, randomized, open-label, multicenter study in 4 parallel groups of kidney transplant recipients. The 1,589 enrolled patients were randomly assigned to receive standard dose CyA, MMF, and CS; or daclizumab induction, MMF, and CS in combination with low-dose CyA, Prograf, or sirolimus (Siro). The primary end point of the study was renal function, measured by estimated glomerular filtration rates, at 12 months after transplantation. Acute rejection, graft survival, and overall mortality were also assessed as secondary end points. Results of the study showed that mortality at 12 months in patients receiving Prograf/MMF (2.7%) was similar to the mortality of patients receiving Cya/MMF (3.3% and 1.8%) or Siro/MMF (3.0%). Patients in the Prograf group exhibited higher estimated creatinine clearance rates (using the Cockcroft-Gault formula) and experienced fewer efficacy failures—defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up—compared with each of the other three groups: Prograf/MMF (20.4%), CyA/MMF (36.2% and 31.6%) and Siro/MMF (46.4%). The median creatinine clearance rate, a measure of kidney function at 12 months, was higher in the Prograf group (66.2 mL/min) than in the other three groups (range, 56.9-60.9 mL/min). The BPAR was also lowest (15.0%) in the Prograf arm when compared with the standard-dose CyA (29.0%), low-dose CyA (26.6%), or sirolimus (38.1%) groups. Graft loss excluding death was also lowest in the low-dose Prograf group (3.0%), followed by the low-dose CyA group (5.0%), the standard-dose CyA group(7.2%), and the Siro group (7.5%).

 

Among a host of adverse effects associated with Prograf, one of the most important is an increased susceptibility to infection and the possible development of lymphoma that may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Prograf.

圣路易斯 (MD Consult) ——2009年5月28日，Astellas公司宣布，美国食品药品管理局(FDA)批准在肾移植受者可以联合应用普乐可复(他克莫司)和霉酚酸酯(MMF)来预防器官排斥反应。1994年，普乐可复获FDA批准，用于预防同种异体肝脏、肾脏或心脏移植患者出现的器官排斥反应。制造商陈述，器官共享联合网络提供的2007年的数据显示，79.3%的肾移植受者出院时接受普乐可复联合霉酚酸酯治疗。

 

FDA批准肾移植受者可应用普乐可复联合霉酚酸酯治疗是依据是大约2,000名肾移植受者参加的两项临床研究。在一项多中心、开放性三期临床试验中，424名肾移植受者接受了普乐可复或环孢素A(Cya)联合霉酚酸酯、舒莱诱导以及皮质类固醇(CS)治疗。研究者报告，在12个月时，普乐可复/霉酚酸酯组与环孢素A/霉酚酸酯组的活检证实的急性排斥、移植物功能衰竭、死亡和/或失访的复合终点事件发生率相似。然而，接受普乐可复/霉酚酸酯治疗的患者在12个月时的死亡率为4.2%，而接受环孢素A/霉酚酸酯的患者的死亡率为2.4%，包括免疫抑制过度的病例。

 

另一项临床试验是对4个平行组的肾移植受者进行的一项前瞻、随机、开放性、多中心的研究。1,589名入选患者随机接受标准剂量的环孢素A、霉酚酸酯和皮质类固醇治疗，或舒莱诱导、霉酚酸酯和皮质类固醇联合低剂量环孢素A、普乐可复或西罗莫司 (Siro)治疗。主要研究终点是肾功能，用移植后12个月时肾小球滤过率的估计值进行评价。急性排斥、移植物存活率和总的死亡率作为次要研究终点进行评价。研究结果显示，接受普乐可复/霉酚酸酯的患者在12个月时的死亡率 (2.7%)与接受环孢素A/霉酚酸酯的患者的死亡率(3.3%和1.8%)或西罗莫司/霉酚酸酯的患者的死亡率(3.0%)相似。同其他3组相比，普乐可复组患者的肌酐清除率的估计值(采用Cockcroft-Gault公式)更高，移植失败率更低(定义为活检证实的急性排斥(BPAR)，移植物失功，死亡和/或失访)：普乐可复/霉酚酸酯组(20.4%)，环孢素A/霉酚酸酯组(36.2%和31.6%)，以及西罗莫司/霉酚酸酯组(46.4%)。12个月时肾功能的评价指标肌酐清除率中位数在普乐可复组为66.2ml/min，高于其他3个组(范围56.9~60.9ml/min)。同标准剂量环孢素A组 (29.0%)，低剂量环孢素A组 (26.6%)或西罗莫司组(38.1%)相比，普乐可复组的活检证实的急性排斥率最低(15.0%)。除外受者死亡的移植物丢失率在低剂量普乐可复组为3.0%，之后是低剂量环孢素A组 (5.0%)，标准剂量环孢素A 组(7.2%)和西罗莫司组(7.5%)。

 

在普乐可复相关的不良反应中，最重要的是免疫抑制导致感染的可能性增加，并且可能会发生淋巴瘤。只有具有免疫抑制和器官移植治疗经验的医生才可处方普乐可复。

 

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