Genotype-Guided Dosing Improves Attainment of Therapeutic Troughs in CYP3A5 Normal Metabolizers After Kidney Transplantation.

Abstract

Purpose: CYP3A5 expressors experience delayed therapeutic tacrolimus concentrations after kidney transplantation, thus, requiring higher tacrolimus doses. Although genotype-guided dosing has demonstrated benefit with immediate-release tacrolimus, data evaluating tacrolimus extended-release (XR) formulations is limited.

Methods: This retrospective, single-center cohort study included adult kidney transplant recipients with CYP3A5 normal or intermediate metabolizer phenotypes initiated on tacrolimus XR between November 2020 and August 2025. Patients received either conventional fixed-dose tacrolimus XR 4 mg daily or genotype-guided dosing (8 mg daily for normal metabolizers and 6 mg daily for intermediate metabolizers). The primary outcome was time to therapeutic tacrolimus trough concentration (≥8 ng/mL). Secondary outcomes included total dose adjustments, rate of supratherapeutic troughs, intrapatient variability, rejection rate, and renal function.

Results: Eighty-one patients met inclusion criteria, including 43 patients in the conventional dosing group and 38 patients in the genotype-guided group. Genotype-guided dosing significantly improved time to therapeutic troughs ≥8 in the normal metabolizers (median 13 vs 25 days; P=0.007), but not in the overall cohort. Both normal and intermediate metabolizers in the genotype-guided group demonstrated significantly higher tacrolimus trough concentrations that were closer to the therapeutic target on post-operative day 3. Genotype-guided dosing was not associated with an increased incidence of supratherapeutic tacrolimus concentrations or adverse clinical outcomes.

Conclusion: Genotype-guided tacrolimus XR dosing improved early tacrolimus concentrations and significantly shortened time to therapeutic trough attainment among CYP3A5 normal metabolizers. These findings support the use of pre-transplant CYP3A5 genotyping to optimize tacrolimus XR dosing in normal metabolizers.