Prolonged-Release Once-Daily Formulation of Tacrolimus Versus Standard-of-Care Tacrolimus in de novo Kidney Transplant Patients Across Europe

Abstract

Background: Tacrolimus is the calcineurin inhibitor of choice for preventing acute rejection episodes in kidney transplant patients. However, tacrolimus has a narrow therapeutic range that requires regular monitoring of blood concentrations to minimize toxicity. A new once-daily tacrolimus formulation, LCP-tacrolimus (LCPT), has been developed, which uses MeltDose™ drug-delivery technology to control drug release and enhance overall bioavailability. Our study compared dosing of LCPT with current standard-of-care tacrolimus [immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac)] during the 6 months following de novo kidney transplantation. Comparisons of graft function, clinical outcomes, safety, and tolerability for LCPT versus IR-Tac/PR-Tac were also performed. Methods: Standard immunological risk patients with end-stage renal disease who had received a de novo kidney transplant were randomized (1:1) to LCPT (N = 200) or IR-Tac/PR-Tac (N = 201). Results: Least squares (LS) mean tacrolimus total daily dose from Week 3 to Month 6 was significantly lower for LCPT than for IR-Tac/PR-Tac. Although LS mean tacrolimus trough levels were significantly higher for LCPT than IR-Tac/PR-Tac, tacrolimus trough levels remained within the standard reference range for most patients. There were no differences between the groups in treatment failure measures or safety profile. Conclusion: LCPT can achieve similar clinical outcomes to other tacrolimus formulations, with a lower daily dose. Clinical Trial Registration: https://ichgcp.net/clinical-trials-registry/NCT02432833" title="See in ClinicalTrials.gov">NCT02432833.

Keywords: LCPT; immunosuppression; kidney; pharmacokinetics; tacrolimus; transplantation.

Conflict of interest statement

GP, DS, SG, CP, and GN are all employees of Chiesi Farmaceutici S.p.A. KB has received honoraria and/or research funding from Alexion, Astellas, Bristol-Myers Squibb, Chiesi, Fresenius, Hansa, Hexal, Merck, Novartis, Otsuka, Pfizer, Roche, Sandoz, Siemens, and Veloxis Pharmaceuticals. UM received participation fees from Chiesi for scientific advisory boards. LR has been an advisor for Hansa and Biotest; has received speaker fees from Astellas, Novartis, Chiesi and Bristol-Myers Squibb; and has received grants from Chugai, Terumo and HemaT. GP, who is now an employee of Chiesi Farmaceutici S.p.A., worked at Dipartimento di Medicina e Chirurgia, UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy at the time of the study and received consulting fees from Chiesi for work as a medical research physician for the present study. OW has received research grants for clinical studies, speaker's fees, honoraria, and travel expenses from Amgen, Astellas, Bristol-Myers Squibb, Chiesi, Hexal, Janssen-Cilag, MSD, Novartis, Pfizer, Roche, and Sanofi. DS received consulting fees from Chiesi for work as a clinical study manager for the present study. NK has received speaker fees and participated in advisory boards for Abbvie, Amgen, Astellas, Chiesi, Fresnius Medical Care, Gilead, Merck Sharp and Dohme, Neovii, Novartis, Roche, Sanofi, and Shire. MB has received funds for travel from Astellas and Chiesi. JP has received consulting fees from Chiesi. DK has received honoraria from Chiesi and Astellas. TW has received honoraria from Chiesi and Therakos/Mallinckrodt, and research funding from Astellas, Chiesi, Neovii, Novartis, Sandoz, Sanofi, and Teva. AG-D has received travel grants, speaker fees, and/or advisory board honoraria from Alexion, Chiesi, MSD and Novartis, and has participated in clinical trials sponsored by Alexion, Astellas, Chiesi and Novartis. LW had received research funding from Chiesi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study (ClinicalTrials.gov, NCT02432833) was funded by Chiesi Farmaceutici SpA. The funder was involved in study design, collection, analysis and interpretation of data. All co-authors have contributed substantially to the analyses and interpretation of the data, and have provided important intellectual input and approval of the final version of the manuscript. Fishawack Inc. has received funding by Chiesi Farmaceutici SpA to provide medical writing support.

Copyright © 2022 Budde, Rostaing, Maggiore, Piotti, Surace, Geraci, Procaccianti, Nicolini, Witzke, Kamar, Albano, Büchler, Pascual, Gutiérrez-Dalmau, Kuypers, Wekerle, Głyda, Carmellini, Tisone, Midtvedt, Wennberg and Grinyó.

Figures

FIGURE 1

Patient disposition. IR-Tac, immediate release tacrolimus; LCPT, LCP tacrolimus; PR-Tac, prolonged release tacrolimus.

FIGURE 2

Tacrolimus total daily dose at each study visit (mean ± SD, mITT). Mean daily dose data was not collected at Day 180. IR-Tac, immediate release tacrolimus; LCPT, LCP tacrolimus; mITT, modified intent-to-treat; PR-Tac, prolonged release tacrolimus; SD, standard deviation.

FIGURE 3

Tacrolimus trough levels (A) and trough:TDD (B) at each study visit (mean ± SD, mITT). IR-Tac, immediate release tacrolimus; LCPT, LCP tacrolimus; mITT, modified intent-to-treat; PR-Tac, prolonged release tacrolimus; SD, standard deviation; TDD, total daily dose.

FIGURE 4

Estimated glomerular filtration rate at each study visit (mean ± SD, mITT). eGFR, estimated glomerular filtration rate; IR-Tac, immediate release tacrolimus; LCPT, LCP tacrolimus; mITT, modified intent-to-treat; PR-Tac, prolonged release tacrolimus; SD, standard deviation.