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

Background. Tacrolimus (Tac) has a narrow therapeutic range. Dosing is generally targeted at Tac trough levels (C0), notwithstanding conflicting reports on the correlation between Tac C0 and systemic exposure measured by the area-under-the-concentration-over-time curve (AUC). The Tac dose required to meet the target C0 varies highly among patients. We hypothesized that patients requiring a relatively high Tac dose for a certain C0 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 C0 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), C0 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 C0, 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 C0 levels are sufficiently reliable to estimate systemic drug exposure. We demonstrated that patients requiring a relatively high Tac dose to attain therapeutic C0 levels have higher drug exposure and could therefore potentially be overdosed.