Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
Department of Pharmacy, University of Oslo, Oslo, Norway.
Clin Transl Sci. 2020 Nov;13(6):1327-1335. doi: 10.1111/cts.12833. Epub 2020 Jul 11.
Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC-guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice-daily tacrolimus in a real-life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting-state and under real-life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting-conditions: 45% higher peak-concentration and 20% higher AUC following the morning dose. In the real-life nonfasting setting, the PK-profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting-state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real-life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting-state, whereas flatter PK-profiles and no circadian variation was present in a real-life, nonfasting setting.
治疗药物监测（TDM）是免疫抑制剂他克莫司（Tac）的强制性要求。为了临床适用性，TDM 使用早晨谷浓度进行。随着最近的发展，使得毛细管微样本中他克莫司浓度的测定和贝叶斯估计器预测浓度-时间曲线下面积（AUC）成为可能，AUC 指导的 TDM 现在可能具有临床适用性。然而，已经报道了他克莫司的昼夜节律变化，在傍晚剂量后，系统暴露量较低。本研究的目的是在没有关于食物和伴随药物时间限制的真实环境中，研究早晨和傍晚两次每日给药后他克莫司的药代动力学（PK）。在移植后早期的 31 例肾移植受者中进行了两次 12 小时的他克莫司研究；分别在空腹状态和真实非禁食状态下（14 例患者重复了该研究），在早晨剂量后和随后的傍晚剂量后进行。我们观察到空腹状态下的昼夜节律变化：早晨剂量后，峰浓度增加 45%，AUC 增加 20%。在现实非禁食环境中，PK 曲线平坦，但与空腹状态相比，早晨和傍晚剂量后 PK 曲线相似，吸收速度较慢，AUC 较低。使用 0、1 和 3 小时时的浓度进行有限采样策略可预测空腹早晨给药后的 AUC，而在其他条件（傍晚和现实非禁食）下，1、3 和 6 小时时的样本可预测 AUC。总之，在处于禁食状态的患者中进行时，他克莫司存在昼夜节律变化，而在现实、非禁食环境中，PK 曲线更平坦，不存在昼夜节律变化。
