Departments of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France.
Unité de Transplantation Rénale, Hôpital Pasteur 2, CHU Nice, Nice, France.
Adv Ther. 2019 Feb;36(2):462-477. doi: 10.1007/s12325-018-0855-1. Epub 2018 Dec 14.
Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus) has not been compared with PR-Tac (Advagraf) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations.
This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations.
PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (t), lower maximum concentration (C) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar.
In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac.
Registered at ClinicalTrials.gov; study number NCT02500212.
Chiesi Farmaceutici S.p.A.
他克莫司有不同的缓控释制剂。迄今为止，LCP-他克莫司（LCPT；Envarsus）的药代动力学（PK）特征尚未在新诊断的肾移植受者中与 PR-Tac（Advagraf）进行比较。这些特征将为指导临床推荐使用每日一次的他克莫司制剂的起始和剂量滴定策略提供依据。
这是一项随机、平行组、开放标签、多中心 PK 研究，将 75 例新诊断的成年白人肾移植受者随机分为 LCPT 0.17mg/kg/天（n=37）或 PR-Tac 0.20mg/kg/天（n=38），治疗 4 周。根据测量的谷浓度，允许进行剂量调整以达到预定义的治疗范围。
PK 分析（第 1、3、7 和 14 天）包括 68 例患者（LCPT，n=33；PR-Tac，n=35）。两组均有相似比例的患者处于预定义的治疗范围内，在研究期间，各有不到 12%的患者谷浓度低于目标值。LCPT 表现出约 30%更高的相对生物利用度[LCPT/PR-Tac 调整后的几何均数比值：第 3 天，1.32（p=0.007）；第 7 天，1.25（p=0.051）；第 14 天，1.43（p=0.002）]和约 30%更低的血药浓度峰谷波动[LCPT/PR-Tac 调整后的几何均数比值：第 3 天，0.70（p<0.001）；第 7 天，0.68（p<0.001）；第 14 天，0.73（p=0.004）]，此外，达到最大血药浓度（t）的时间更长，最大浓度（C）更低，每日剂量也持续降低（与 PR-Tac 相比，第 28 天 LCPT 降低约 40%）。安全性特征相似。
在新诊断的肾移植受者中，他克莫司的缓控释制剂可以在移植后立即达到治疗浓度。LCPT 的相对生物利用度更高，峰谷波动比 PR-Tac 更低。
ClinicalTrials.gov 注册；研究编号 NCT02500212。
Chiesi Farmaceutici S.p.A.
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