Effectiveness of Tacrolimus Loading Doses to Achieve Target Tacrolimus Trough Concentrations

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Introduction Tacrolimus is widely utilized for graft versus host disease (GVHD) prophylaxis following allogeneic hematopoietic cell transplantation (allo-HCT). Studies have shown that achieving early therapeutic tacrolimus trough concentrations can reduce the risk of GVHD, however given its narrow therapeutic index , determining appropriate dosing to achieve therapeutic concentrations remains challenging. The current standard dosing (SD) approach for tacrolimus dosing is weight-based at either 0.03 mg/kg/day continuous IV infusion or 0.03 mg/kg orally twice daily (BID). To decrease the time to achieve a therapeutic trough concentration, our institution adopted a modified dosing approach of a loading dose (LD) of oral tacrolimus 0.045 mg/kg BID for 4 doses followed by 0.03 mg/kg BID. This study assessed the impact of the LD dosing regimen on tacrolimus concentrations. Objective To evaluate the efficacy of the LD-based strategy for tacrolimus dosing Methods This single-center retrospective study evaluated adult patients who underwent an allo-HCT at our institution between April 2014 and June 2024 and received oral tacrolimus as part of their GVHD prophylaxis. Patients were stratified by whether they received SD or LD dosing. The primary endpoint was time to trough concentration ≥ 5 ng/mL. Secondary endpoints included time to therapeutic trough concentration (5-10 ng/mL) and percentage of patients in therapeutic range at the first through third troughs. Time to event analyses were performed using log-rank tests and Kaplan Meier plots visually represented cumulative incidence Chi-square tests were used to evaluate differences in percentage of subjects ≥5 ng/mL between LD and SD groups. Results A total of 532 patients met inclusion criteria, with 346 receiving SD and 186 receiving LD. The median first trough was 3.1 ng/mL (range: 0.4-17.2) and 4.4 ng/mL (range: 0.9-24.7) for SD and LD, respectively (P < 0.001). The time from initiation to a trough of ≥ 5 ng/mL was longer in SD (5 days) versus LD (4 days, HR=0.79, 95% CI 0.66-0.95; P=0.003). The time from initiation to therapeutic trough was longer in SD (6 days) versus LD (4 days, HR=0.78, 95% CI 0.65-0.94; P=0.002). Significantly more patients in the SD group had a subtherapeutic initial trough compared to LD (Table 1). In patients achieving a stable tacrolimus dose, those in the SD group had a weight-based oral dose of 0.023 mg/kg BID compared to 0.027 mg/kg BID in the LD group (P=0.12) Conclusion The LD approach resulted in a significant reduction in the time to achieve both a trough concentration ≥ 5 ng/mL and a therapeutic trough as well as more patients achieving an initial trough of ≥ 5 ng/mL. The stable, weight-based dose was less than 0.03 mg/kg BID in both groups and was not statistically different. The long-term impact of the LD strategy, potential toxicities, and changes in dose modification strategy warrants further evaluation.

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