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. METHODS. We retrospectively analyzed data from 53 patients in which a 24-h Tac AUC(24) 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 AUC(24) 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 AUC(24) 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 AUC(24) 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.