Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 29;9(4):e1439.
doi: 10.1097/TXD.0000000000001439. eCollection 2023 Apr.

Does the Tacrolimus Trough Level Adequately Predict Drug Exposure in Patients Requiring a High Tacrolimus Dose?

Lien Haverals  1 , Laurence Roosens  2 , Kristien Wouters  3 , Pierre Marquet  4 , Caroline Monchaud  4 , Annick Massart  1 , Daniel Abramowicz  1   5 , Rachel Hellemans  1   5
Affiliations

Does the Tacrolimus Trough Level Adequately Predict Drug Exposure in Patients Requiring a High Tacrolimus Dose?

Lien Haverals et al. Transplant Direct. .

Abstract

Tacrolimus (Tac) has a narrow therapeutic range. Dosing is generally targeted at Tac trough levels (C 0), notwithstanding conflicting reports on the correlation between Tac C 0 and systemic exposure measured by the area-under-the-concentration-over-time curve (AUC). The Tac dose required to meet the target C 0 varies highly among patients. We hypothesized that patients requiring a relatively high Tac dose for a certain C 0 may show a higher AUC.

Methods: We retrospectively analyzed data from 53 patients in which a 24-h Tac AUC24 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 C 0 and AUC24 changes according to dose level.

Results: Despite the large difference in mean Tac dose between the low- and high-dose group (7 versus 17 mg/d), C 0 levels were similar. However, the mean AUC24 was substantially higher in the high-dose group (320 ± 96 h·μg/L versus 255 ± 81 h·μg/L, P < 0.001). This difference remained significant after adjusting for age and race. For a same C 0, every 0.01 mg/kg increase in Tac dose resulted in an AUC24 increase of 3.59 h·μg/L.

Conclusions: This study challenges the general belief that C 0 levels are sufficiently reliable to estimate systemic drug exposure. We demonstrated that patients requiring a relatively high Tac dose to attain therapeutic C 0 levels have higher drug exposure and could therefore potentially be overdosed.

PubMed Disclaimer

Conflict of interest statement

The authors declare no funding or conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
A blood-concentration time curve for a Tac dose ≤0.15 mg/kg and a Tac dose >0.15 mg/kg (error bars represent SD of the mean). *Statistically significant. Tac, tacrolimus.
FIGURE 2.
FIGURE 2.
Scatterplot graph showing the association between the C0 and AUC24 in 36 patients with a low dose of Tac (▽) and in 17 patients with a high dose of Tac (•). The dotted line indicates the regression equation. AUC, area-under-the-concentration-over-time curve; Tac, tacrolimus.
See this image and copyright information in PMC

References

    1. Ekberg H, Tedesco-Silva H, Demirbas A, et al. . Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357:2562–2575. - PubMed
    1. Caillard S, Moulin B, Buron F, et al. . Advagraf, a once-daily prolonged release tacrolimus formulation, in kidney transplantation: literature review and guidelines from a panel of experts. Transpl Int. 2016;29:860–869. - PubMed
    1. Albano L, Banas B, Klempnauer JL, et al. . OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. Transplantation. 2013;96:897–903. - PMC - PubMed
    1. Tuteja S, Alloway RR, Johnson JA, et al. . The effect of gut metabolism on tacrolimus bioavailability in renal transplant recipients. Transplantation. 2001;71:1303–1307. - PubMed
    1. Scholten EM, Cremers SC, Schoemaker RC, et al. . AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients. Kidney Int. 2005;67:2440–2447. - PubMed