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 (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 center dot mu g/L versus 255 +/- 81 h center dot mu g/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 center dot mu g/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.