BACKGROUND: Available tacrolimus formulations exhibit substantial inter- and intra-individual variability in absorption and metabolism. The present non-interventional cohort study aimed to assess the tolerability and effectiveness of the once-daily tacrolimus formulation, LCPT, in hepatic allograft recipients in real life. MATERIALS AND METHODS: This study was conducted in Austria and the Czech Republic between July 2016 and August 2019. Patients aged ≥ 18 years old received LCPT per the approved label and local clinical routine. All the participants provided informed consent. Patients newly treated with tacrolimus (de novo) directly after transplantation were observed for six months. The relevant clinical variables were tacrolimus trough level (TL), total daily dose (TDD), number of dose adjustments, kidney and liver function, and tolerability. RESULTS: Of the 70 analyzed patients, 72.9% were male and 85.7% were aged < 65 years old. The mean (SD) time to achieve tacrolimus target TL was 6.4 (4.6) days after 4.4 (4.0) dose adjustments; thereafter, TL remained stable throughout observation at approximately 8 ng/mL. The LCPT TDD at initiation was 8 mg and decreased by a median of 41.4% to 5 mg at 6 months. Liver function continuously improved, and kidney function remained stable. LCPT was well tolerated with 24 adverse events in eight patients (17 related to immunosuppression, mostly mild renal insufficiency, and hematological adverse events); two serious unrelated adverse events were reported (atrial flutter and liver dysfunction). CONCLUSIONS: TL was rapidly attained with few dose adaptations after LCPT initiation in de novo liver transplant patients. Liver function rapidly improved, whereas kidney function remained normal. LCPT was well-tolerated in this population.

Center for Cardiovascular and Transplantation Surgery 602 00 Brno Czech Republic

Department of Surgery Division of Transplantation Medical University of Vienna Waehringer Guertel 18 20 1090 Vienna Austria

Zobrazit více v PubMed

Wagner M., Earley A.K., Webster A.C., Schmid C.H., Balk E.M., Uhlig K. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst. Rev. 2015:CD007746. doi: 10.1002/14651858.CD007746.pub2. PubMed DOI PMC

Di Maira T., Little E.C., Berenguer M. Immunosuppression in liver transplant. Best Pract. Res. Clin. Gastroenterol. 2020;46–47:101681. doi: 10.1016/j.bpg.2020.101681. PubMed DOI

Jasiak N.M., Park J.M. Immunosuppression in Solid-Organ Transplantation: Essentials and Practical Tips. Crit. Care Nurs. Q. 2016;39:227–240. doi: 10.1097/CNQ.0000000000000117. PubMed DOI

Thomson A.W., Bonham C.A., Zeevi A. Mode of action of tacrolimus (FK506): Molecular and cellular mechanisms. Ther. Drug Monit. 1995;17:584–591. doi: 10.1097/00007691-199512000-00007. PubMed DOI

Vicari-Christensen M., Repper S., Basile S., Young D. Tacrolimus: Review of pharmacokinetics, pharmacodynamics, and pharmacogenetics to facilitate practitioners’ understanding and offer strategies for educating patients and promoting adherence. Prog. Transplant. 2009;19:277–284. doi: 10.1177/152692480901900315. PubMed DOI

Venkataramanan R., Swaminathan A., Prasad T., Jain A., Zuckerman S., Warty V., McMichael J., Lever J., Burckart G., Starzl T. Clinical pharmacokinetics of tacrolimus. Clin. Pharmacokinet. 1995;29:404–430. doi: 10.2165/00003088-199529060-00003. PubMed DOI

European Medicines Agency Envarsus: EPAR—Product Information. [(accessed on 29 May 2020)]; Available online: https://www.ema.europa.eu/en/documents/product-information/envarsus-epar-product-information_en.pdf.

Wallemacq P., Armstrong V.W., Brunet M., Haufroid V., Holt D.W., Johnston A., Kuypers D., Meur Y.L., Marquet P., Oellerich M., et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: Report of the European consensus conference. Ther. Drug Monit. 2009;31:139–152. doi: 10.1097/FTD.0b013e318198d092. PubMed DOI

Grinyo J.M., Petruzzelli S. Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations. Expert Rev. Clin. Immunol. 2014;10:1567–1579. doi: 10.1586/1744666X.2014.983903. PubMed DOI

Tremblay S., Nigro V., Weinberg J., Woodle E.S., Alloway R.R. A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study. Am. J. Transplant. 2017;17:432–442. doi: 10.1111/ajt.13935. PubMed DOI PMC

Garnock-Jones K.P. Tacrolimus prolonged release (Envarsus(R)): A review of its use in kidney and liver transplant recipients. Drugs. 2015;75:309–320. doi: 10.1007/s40265-015-0349-2. PubMed DOI

European Medicines Agency Guideline on Clinical Investigation of Immunosuppressants for Solid Organ Transplantation. [(accessed on 2 July 2020)]; Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-immunosuppressants-solid-organ-transplantation_en.pdf.

von Elm E., Altman D.G., Egger M., Pocock S.J., Gøtzsche P.C., Vandenbroucke J.P. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Lancet. 2007;370:1453–1457. doi: 10.1016/S0140-6736(07)61602-X. PubMed DOI

Gaber A.O., Alloway R.R., Bodziak K., Kaplan B., Bunnapradist S. Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): A phase 2 trial of stable renal transplant recipients. Transplantation. 2013;96:191–197. doi: 10.1097/TP.0b013e3182962cc1. PubMed DOI PMC

DuBay D.A., Teperman L., Ueda K., Silverman A., Chapman W., Alsina A.E., Tyler C., Stevens D.R. Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets versus Twice-Daily Capsules in De Novo Liver Transplant. Clin. Pharmacol. Drug Dev. 2019;8:995–1008. doi: 10.1002/cpdd.657. PubMed DOI PMC

Baccarani U., Velkoski J., Pravisani R., Adani G.L., Lorenzin D., Cherchi V., Falzone B., Baraldo M., Risaliti A. MeltDose Technology vs. Once-Daily Prolonged Release Tacrolimus in De Novo Liver Transplant Recipients. Transplant. Proc. 2019;51:2971–2973. doi: 10.1016/j.transproceed.2019.03.084. PubMed DOI

Mercuri A., Wu S., Stranzinger S., Mohr S., Salar-Behzadi S., Bresciani M., Fröhlich E. In vitro and in silico characterisation of Tacrolimus released under biorelevant conditions. Int. J. Pharm. 2016;515:271–280. doi: 10.1016/j.ijpharm.2016.10.020. PubMed DOI

Alloway R.R., Eckhoff D.E., Washburn W.K., Teperman L.W. Conversion from twice daily tacrolimus capsules to once daily extended-release tacrolimus (LCP-Tacro): Phase 2 trial of stable liver transplant recipients. Liver Transplant. 2014;20:564–575. doi: 10.1002/lt.23844. PubMed DOI

Hazell L., Shakir S.A.W. Under-Reporting of Adverse Drug Reactions. Drug Saf. 2006;29:385–396. doi: 10.2165/00002018-200629050-00003. PubMed DOI