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

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.

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.

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.

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.