Haverals Lien, Roosens Laurence, Wouters Kristien, Marquet Pierre, Monchaud Caroline, Massart Annick, Abramowicz Daniel, Hellemans Rachel
Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.
Department of Clinical and Biological Sciences, Antwerp University Hospital, Edegem, Belgium.
Transplant Direct. 2023 Mar 29;9(4):e1439. doi: 10.1097/TXD.0000000000001439. eCollection 2023 Apr.
Tacrolimus (Tac) has a narrow therapeutic range. Dosing is generally targeted at Tac trough levels ( ), notwithstanding conflicting reports on the correlation between Tac and systemic exposure measured by the area-under-the-concentration-over-time curve (AUC). The Tac dose required to meet the target varies highly among patients. We hypothesized that patients requiring a relatively high Tac dose for a certain may show a higher AUC.
We retrospectively analyzed data from 53 patients in which a 24-h Tac AUC estimation was performed at our center. Patients were divided into those taking a low (≤0.15 mg/kg) or high (>0.15 mg/kg) once-daily Tac dose. Multiple linear regression models were used to investigate if the association between and AUC changes according to dose level.
Despite the large difference in mean Tac dose between the low- and high-dose group (7 versus 17 mg/d), levels were similar. However, the mean AUC was substantially higher in the high-dose group (320 ± 96 h·μg/L versus 255 ± 81 h·μg/L, < 0.001). This difference remained significant after adjusting for age and race. For a same , every 0.01 mg/kg increase in Tac dose resulted in an AUC increase of 3.59 h·μg/L.
This study challenges the general belief that levels are sufficiently reliable to estimate systemic drug exposure. We demonstrated that patients requiring a relatively high Tac dose to attain therapeutic levels have higher drug exposure and could therefore potentially be overdosed.
他克莫司（Tac）的治疗窗较窄。尽管关于Tac谷浓度（ ）与通过浓度-时间曲线下面积（AUC）测量的全身暴露之间的相关性存在相互矛盾的报道，但给药通常以Tac谷浓度为目标。达到目标 所需的Tac剂量在患者之间差异很大。我们假设，对于特定的 ，需要相对高剂量Tac的患者可能具有较高的AUC。
我们回顾性分析了在我们中心进行24小时Tac AUC估算的53例患者的数据。患者被分为每日一次服用低剂量（≤0.15mg/kg）或高剂量（>0.15mg/kg）Tac的患者。使用多元线性回归模型来研究 与根据剂量水平变化的AUC之间的关联。
尽管低剂量组和高剂量组之间的平均Tac剂量差异很大（7mg/d对17mg/d），但 水平相似。然而，高剂量组的平均AUC显著更高（320±96h·μg/L对255±81h·μg/L， <0.001）。在调整年龄和种族后，这种差异仍然显著。对于相同的 ，Tac剂量每增加0.01mg/kg，AUC增加3.59h·μg/L。
本研究挑战了普遍观点，即 水平足以可靠地估计全身药物暴露。我们证明，需要相对高剂量Tac才能达到治疗 水平的患者具有更高的药物暴露，因此可能存在用药过量的情况。
