Pharmacokinetic study of once-daily formulation of tacrolimus (Advagraf) in stable Chinese kidney transplant recipients

Abstract

Background/Purpose

The objective of this study is to determine whether tacrolimus trough level is appropriate for therapeutic drug monitoring (TDM) of Advagraf in stable Chinese kidney transplant recipients (KTRs).

Methods

In this single-center pharmacokinetic study, stable adult Chinese KTRs on Advagraf were recruited and their blood tacrolimus levels measured at 12 time points within 24 hours. Trough level was defined as predose drug level (C₀). The pharmacokinetic parameters were calculated using standardized noncompartmental methods. Drug exposure, defined as 24-hour area under the curve (AUC_0–24), was calculated using the linear trapezoidal method. Whole blood tacrolimus level measurement was performed by high-performance liquid chromatography/tandem mass spectrophotometry.

Results

Fourteen patients (8 males; mean age, 47.1 ± 9.2 years; mean duration of transplant, 8.3 ± 3.6 years) completed the study. The mean C₀ was 4.4 ± 1.9 ng/mL, and the mean AUC_0–24 was 143.8 ± 57.0 ng h/mL. The mean maximum concentration (C_max) was 10.2 ± 3.9 ng/mL, and the median time to C_max was 2.0 hours (interquartile range, 1.0–3.0 hours). There was a strong correlation between C₀ and AUC_0–24 (r = 0.90, p < 0.001). Patients receiving diltiazem had higher mean AUC_0–24 (153.0 ± 55.3 ng h/mL vs. 110.1 ± 60.1 ng h/mL) despite a lower dose (mean tacrolimus dose, 0.039 ± 0.022 mg/kg/d vs. 0.054 ± 0.021 mg/kg/d), although both differences did not reach statistical significance. Apart from C₀, tacrolimus level obtained from 6 hours to 12 hours (C₆ to C₁₂) also had good correlation with AUC_0–24.

Conclusion

Tacrolimus trough level is a good surrogate marker for TDM of Advagraf in stable Chinese KTRs. The role of C₆ to C₁₂ in TDM remains to be determined.

背景 / 目的

本研究旨在調查在病情穩定的華裔腎臟移植接受者 (KTRs) 間,Cmin 是否適用於藥物血中濃度監測 (TDM)。

方法

在這一項單中心藥物動力學研究中,對象為病情穩定的華裔 KTRs,在 24 小時內 12 個時間點接受了動脈血的取樣,谷值的定義為服藥前藥物濃度 (C0)。藥物動力學參數的計算是採用標準化無房室模式,AUC0–24 的計算採用線性梯形方式。全血 tacrolimus 濃度的測量儀器,則是採用高效能液相色層分析串聯質譜儀 (HPLCMS/MS)。

結果

本研究共納入 14 位服用 Advagraf^® 的病人,平均 C0 為 4.4 ± 1.9 ng/ml,平均 AUC0–24 為 143.8 ± 57.0 ng·h/ml,平均最高濃度 Cmax 為 10.2 ± 3.9 ng/ml,達到 Cmax 的時間中位數 tmax 則為 2.0 小時 (四分位數間距 1.0–3.0 小時);C0 與 AUC0–24 存在明顯的相關性 (r = 0.90、p < 0.001)。在接受 diltiazem 的病人中,平均 AUC0–24 較高 (153.0 ± 55.3 ng·h/ml vs. 110.1 ± 60.1 ng·h/ml),即使他們服用較低的 tacrolimus 劑量 (平均劑量 0.039 ± 0.022 mg/kg/day vs. 0.054 ± 0.021 mg/kg/day);這兩種差異未達統計學意義。除了 C0 之外,6 至 12 小時 (C6 to C12) 之 tacrolimus 濃度亦與 AUC0–24 存在顯著的相關性。

結論

對於病情穩定的華裔 KTRs,tacrolimus 谷值乃 AUC0–24 的一個良好替代指標;至於 C6 to C12 的角色則仍有待證實。