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Original Article

Korean J Transplant 2019; 33(2): 20-29

Published online June 30, 2019


© The Korean Society for Transplantation

Efficacy and safety of prolonged-release versus immediate-release tacrolimus in de novo liver transplant recipients in South Korea: a randomized open-label phase 4 study (MAPLE)

Myoung Soo Kim1, Jae-Won Joh2, Dong-Sik Kim3, Seoung Hoon Kim4, Jin Sub Choi5, Jaegeun Lee1, Jee Youn Lee6, Jong Man Kim2, Choon Hyuck David Kwon2, Gyu-Seong Choi2, Young Dong Yu7, Yong-In Yoon8, Jae Hyun Han9, Yun Jeong Lee10, Hongsi Jiang11, Soon-Il Kim1

1Department of Transplant Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 2Department of Surgery, Samsung Medical Center, Seoul, Korea; 3Department of Surgery, Korea University College of Medicine, Seoul, Korea; 4Department of Hepatobiliary Surgery, National Cancer Center, Seoul, Korea; 5Department of Hepatobiliary-Pancreas Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 6Department of Surgery, Kangbuk Samsung Hospital, Seoul, Korea; 7Department of Hepatobiliary Surgery, Korea University Anam Hospital, Seoul, Korea; 8Department of Hepatobiliary Surgery, Asan Medical Center, Seoul, Korea; 9Department of Surgery, St. Vincent's Hospital, The Catholic University of Korea, Seoul, Korea; 10Astellas Pharma Inc., Seoul, Korea; 11Astellas Pharma Inc., Singapore

Correspondence to: Soon-Il Kim Department of Transplant Surgery, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03772, Korea Tel: +82-2-2228-2118, Fax: +82-2-313-8239, E-mail: soonkim@yuhs.ac

Received: September 27, 2018; Revised: March 27, 2019; Accepted: March 31, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Background: Prolonged-release tacrolimus is associated with better long-term graft and patient survival than the immediate-release formulation in liver transplant patients. However, no clinical data are available to assess the efficacy and safety of early conversion from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus in de novo liver transplant recipients in Korea.
Methods: A 24-week, randomized, open-label study was conducted in 36 liver transplant recipients. All patients received immediaterelease tacrolimus (0.1?0.2 mg/kg/day, divided into two doses) for 4 weeks after transplantation, at which time 50% of the patients were converted, at a ratio of 1 mg to 1 mg, to prolonged-release tacrolimus (once-daily). The primary efficacy endpoint was the incidence of biopsy-confirmed acute rejection (BCAR) from weeks 4 to 24 after transplantation (per-protocol set). Medication adherence, adverse event profiles, laboratory tests, vital signs, and physical changes were also recorded.
Results: BCAR frequency at 24 weeks was similar between the two treatment groups; two cases (mean±standard deviation, 0.14±0.53 cases) of BCAR were reported in one patient treated with prolonged-release tacrolimus (n=14), while no such cases were reported among patients treated with immediate-release tacrolimus (n=12). The tacrolimus blood concentration at weeks 12 and 24, medication adherence, and adverse event profiles were also similar between the formulations, with no unusual laboratory test results, vital signs, or physical changes reported.
Conclusions: Early conversion to a simplified, once-daily, prolonged-release tacrolimus regimen may be an effective treatment option for liver transplant recipients in Korea. Larger-scale studies are warranted to confirm non-inferiority to immediate-release tacrolimus formulation in de novo liver transplant recipients.

Keywords: Immunosuppressive agents, Humans, Liver transplantation, Prolonged-release tacrolimus, Republic of Korea, Treatment outcome