Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, QLD, Australia.
Drugs. 2011 Aug 20;71(12):1561-77. doi: 10.2165/11593890-000000000-00000.
Tacrolimus is a cornerstone immunosuppressant agent in the prevention of organ rejection following transplantation. While typically administered twice daily (Prograf®), a modified-release once-daily formulation (Advagraf®) has recently been developed and licensed for use. To date, the majority of published data relating to the use of Advagraf® have arisen from industry-sponsored clinical trials. These have shown that conversion from Prograf® to Advagraf® on a 1 mg : 1 mg basis in both stable and de novo kidney and liver transplant recipients yields lower peak concentrations (C(max)) but equivalent overall drug exposure (area under the concentration-time curve from 0 to 24 hours post-dose; AUC(24)) and trough concentrations (C(min)). This has led to the proposal that the same total daily dose, target C(min) and therapeutic drug monitoring (TDM) strategies can be applied irrespective of preparation. However, while Advagraf® fulfils criteria for bioequivalence according to the European Medicines Agency and US FDA, lower tacrolimus exposure has been observed in the majority of clinical studies, particularly in the early post-transplant period. This has resulted in a need for higher doses of Advagraf® compared with Prograf® to achieve similar C(min) values. Significant between-subject variability in the C(min)/AUC(24) relationship with Advagraf® has also been demonstrated, suggesting possible problems with TDM based on C(min) values. In non-comparative conversion studies, Advagraf® demonstrated similar efficacy and safety to Prograf®. However, phase III studies in de novo kidney and liver transplant recipients have shown higher rates of acute rejection with Advagraf®, possibly explained by the differing C(max) values achieved with the two preparations. While it has been suggested that once-daily administration may improve compliance, no studies have proven this to be the case. This article reviews the pharmacokinetics, efficacy, adverse effects and utility of Advagraf® in relation to its equivalence to Prograf®, and areas that require additional research are identified.
他克莫司是器官移植后预防排斥反应的基石免疫抑制剂。虽然通常每日两次给药（普乐可复®），但最近已开发并获得许可用于一种改良的每日一次制剂（Advagraf®）。迄今为止，与 Advagraf®使用相关的大多数已发表数据来自于行业赞助的临床试验。这些试验表明，在稳定和新诊断的肾和肝移植受者中，从普乐可复®转换为 Advagraf®，基于 1 毫克：1 毫克的剂量，可降低峰浓度（Cmax），但等效的总体药物暴露（0 至 24 小时后剂量的浓度-时间曲线下面积；AUC（24））和谷浓度（Cmin）。这导致提出可以应用相同的总日剂量、目标 Cmin 和治疗药物监测（TDM）策略，而与制剂无关。然而，虽然 Advagraf®根据欧洲药品管理局和美国食品药品监督管理局的标准符合生物等效性的标准，但在大多数临床研究中，尤其是在移植后早期，观察到的他克莫司暴露水平较低。这导致与普乐可复®相比，需要更高剂量的 Advagraf®才能达到相似的 Cmin 值。在 Advagraf®的 Cmin/AUC（24）关系中，还显示出明显的个体间变异性，这表明基于 Cmin 值的 TDM 可能存在问题。在非对照转换研究中，Advagraf®显示出与普乐可复®相似的疗效和安全性。然而，在新诊断的肾和肝移植受者的 III 期研究中，Advagraf®显示出更高的急性排斥反应率，这可能与两种制剂达到的 Cmax 值不同有关。虽然有人认为每日一次给药可能会提高依从性，但没有研究证明这一点。本文综述了 Advagraf®与普乐可复®等效性相关的药代动力学、疗效、不良反应和实用性，以及需要进一步研究的领域。
