Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study

Abstract

Introduction

Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus^®) has not been compared with PR-Tac (Advagraf^®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations.

Methods

This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations.

Results

PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (t_max), lower maximum concentration (C_max) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar.

Conclusion

In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac.

Trial registration

Registered at ClinicalTrials.gov; study number NCT02500212.

Funding

Chiesi Farmaceutici S.p.A.

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