Early twice-daily dosing of extended-release tacrolimus improves target trough attainment after kidney transplantation: A prospective randomized controlled study

Background: Extended-release tacrolimus is generally administered once daily, but early post-transplant target trough concentration attainment may be delayed in some kidney transplant recipients. This study evaluated whether an early twice-daily dosing strategy could improve rapid target attainment of extended-release tacrolimus after kidney transplantation.
Methods: This single-center, prospective, open-label, randomized controlled study enrolled adult first kidney transplant recipients receiving extended-release tacrolimus-based initial immunosuppression. Recipients were randomized to a twice-daily dosing group or a once-daily dosing group. Initial doses were determined according to CYP3A5 metabolizer status: poor metabolizers received 0.05 mg/kg twice daily in the twice-daily group or 0.10 mg/kg once daily in the once-daily group, while intermediate or rapid metabolizers received 0.075 mg/kg twice daily or 0.15 mg/kg once daily, respectively. The primary endpoint was tacrolimus trough concentration target attainment on postoperative day 4, defined as 8–15 ng/mL. Logistic regression was used to assess the association between dosing strategy and target attainment, with adjustment for CYP3A5 metabolizer status and baseline hematocrit.
Results: A total of 63 recipients were included, with 32 in the twice-daily group and 31 in the once-daily group. On postoperative day 4, tacrolimus trough concentration was higher in the twice-daily group than in the once-daily group [9.30 (8.45, 10.90) vs 7.90 (6.20, 9.70) ng/mL, p = 0.013]. Target attainment was also higher with twice-daily dosing than with once-daily dosing [25/32 (78.1%) vs 15/31 (48.4%), p = 0.019]. The proportion of recipients below the target range was 18.8% and 51.7%, respectively. On postoperative day 4, tacrolimus trough concentration >15 ng/mL was observed in 1 recipient in each group [1/32 (3.1%) vs 1/31 (3.2%), p = 1.000]. In logistic regression analysis, twice-daily dosing was associated with target attainment in the crude model (OR 3.83, 95% CI 1.26–11.62, p = 0.018) and after adjustment for CYP3A5 metabolizer status and baseline hematocrit (adjusted OR 4.02, 95% CI 1.25–12.98, p = 0.020). Postoperative day 7 and day 14 serum creatinine, delayed graft function, acute rejection, pulmonary infection, hyperglycemia, poor wound healing, and diarrhea did not differ significantly between groups.
Conclusions: Early twice-daily dosing of extended-release tacrolimus improved postoperative day 4 target trough concentration attainment after kidney transplantation without an apparent increase in short-term safety concerns. This strategy appears feasible for early tacrolimus initiation, but larger studies with longer follow-up and pharmacokinetic assessment are warranted.