Outcomes of Early Conversion From Prograf to Generic Tacrolimus in Adult Living Donor Liver Transplant Recipients S.H. Kima,*, S.D. Leea, Y.K. Kimb, and S.J. Parka a Center for Liver Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea; and bDepartment of Surgery, College of Medicine, Jeju National University, Jeju-do, Republic of Korea
ABSTRACT The aim of this study was to evaluate the safety and efﬁcacy of early conversion from the reference tacrolimus (Prograf; Astellas Pharma, Tokyo, Japan) to the generic tacrolimus (Tacrobell:Chong Kun Dang Pharma, Seoul, Korea) in a cohort of adult living donor liver transplant (LDLT) recipients at a single institution. Between March 2010 and May 2012, a 1:1 dose conversion was performed 2 to 4 weeks after LDLT with dose adjustments targeted to achieve trough concentrations within the therapeutic range. Tacrolimus doses and trough levels, laboratory parameters, and adverse events were assessed. A total of 149 patients were enrolled. The median transplant duration was 22 days (range; 15e28 days). During a median follow-up of 17.3 months after conversion, there were 3 episodes of acute rejection, all of which responded to high-dose steroids. No adverse events were serious enough to stop the drug. In comparison with the control group maintained on Prograf, there were no signiﬁcant differences in outcomes. In conclusion, early conversion from the reference to generic tacrolimus is safe and effective in stable adult LDLT patients.
ACROLIMUS is an effective immunosuppressant well established in solid organ transplantation . A generic tacrolimus, Tacrobell (Chong Kun Dang Pharmaceutical, Corp., Seoul, Korea), was approved in 2006 by the Korea Food and Drug Administration. Currently there is a paucity of data related to the safety and efﬁcacy of switching living donor liver transplant (LDLT) patients from the reference tacrolimus product (Prograf; Astellas Pharma, Tokyo, Japan) to the recently available generic formulation. In this study, the impact of generic substitution 2 to 4 weeks after LDLT on tacrolimus doses and trough concentrations, laboratory parameters, and adverse events was investigated in clinically stable LDLT recipients.
PATIENTS AND METHODS This was a single-institution retrospective cohort study conducted with adult patients who underwent LDLT and were followed as outpatients in National Cancer Center in Goyang, South Korea. The conversion from Prograf to Tacrobell was performed between March 2010 and May 2012. The study subjects were ABOcompatible LDLT recipients with normal liver and renal function, stable tacrolimus dosage prior to the switch, and no previous rejection episodes. The switching policy was based on a dose ratio of 1:1 with the dose adjustments based on the target tacrolimus trough levels that were 8e13 ng/mL for the ﬁrst 3 months,
6e8 ng/mL for months 3e6, and 3e6 ng/mL thereafter. Mycophenolate mofetil was added 2 days after LDLT at a dosage of 1.5 g/day and titrated according to white blood cell count. Steroids were tapered to discontinuation by 3 months after LDLT. Tacrolimus doses and trough levels, laboratory parameters, and adverse events were assessed. These outcome measures were compared with those of LDLT recipients maintained on the brand tacrolimus who were retrieved from our LDLT database. Variables were compared with the Student t test and the c2 test, and P values <.05 were considered signiﬁcant.
A total of 149 patients were enrolled. The 107 male and 42 female subjects had a median age at the time of switch of 52 years (range 36e70). The median time to conversion after LDLT was 22 days (range; 15-28 days). During a median follow-up of 17.3 months (range 12.5e23.7 months) after conversion, the target tacrolimus blood trough levels were achieved by dose adjustments. Liver and renal function tests
*Address correspondence to Seong Hoon Kim, MD, PhD, Center for Liver Cancer, National Cancer Center, 111 Jungbalsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Republic of Korea. E-mail: [email protected]
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Transplantation Proceedings, 47, 1915e1916 (2015)
KIM, LEE, KIM ET AL
Fig 1. Mean trough level (left) and daily dosage (right) of tacrolimus during study.
remained stable. There were 3 episodes of acute rejection, all of which responded to high-dose steroids. No adverse events were serious enough to stop the drug. The control group consisted of 129 LDLT patients. Both groups were well balanced with respect to age, gender, disease type, MELD score, and graft-to-recipient weight ratio, with no signiﬁcant differences between the 2 groups. There were no
Table 1. Adverse Events During the Study Period
Acute rejection*, n (%) Hepatic dysfunction†, n (%) Renal dysfunction‡, n (%) PTDM§, n (%) Hyperlipidemia¶, n (%) Diarrhea, n (%) Tremor, n (%) Headache, n (%) Hair loss, n (%) Skin rash, n (%)
Generic Group (n ¼ 149)
3 (2.0) 6 3 14 8 12 4 12 6
(4.0) (2.0) (9.4) (5.4) (8.1) (2.7) (8.1) (4.0)
Brand Group (n ¼ 129)
4 3 12 9 12 5 13 7
(3.1) (2.3) (9.3) (7.0) (9.3) (3.9) (10.1) (5.4)
.9278 .8148 .8573 .7589 .8764 .8259 .7054 .7901
Acute rejection* was deﬁned according to the Banff criteria on liver biopsy. Hepatic dysfunction† includes liver enzyme elevations. Renal dysfunction‡ was deﬁned as estimated GFR (MDRD) < 60 mL/min/1.73 m2 (GFR, glomerular ﬁltration rate; MDRD, the Modiﬁcation of Diet in Renal Disease Study equation). PTDM§ (posttransplant diabetes mellitus) was deﬁned according to the American Diabetes Association Diagnostic Criteria. Hyperlipidemia¶ was deﬁned as hypercholesterolemia >240 mg/dL and hypertriglyceridemia >200 mg/dL, or as the use of a hypolipidemic treatment.
signiﬁcant differences in terms of tacrolimus doses and trough concentrations (Fig 1). Laboratory parameters and adverse events also showed no appreciable differences between the brand and generic groups (Table 1).
This study examined the safety and efﬁcacy of generic substitution of tacrolimus with Tacrobell 2 to 4 weeks after LDLT, when most recipients could be discharged for outpatient follow-up. These results can be corroborated with a recent ﬁnding that a generic conversion did not result in adverse clinical events . Although the less than 2-year follow-up does not allow conclusions to be made about the long-term safety or effectiveness of generic tacrolimus, these results provide clinical data to dispel misconceptions that generic tacrolimus is inherently inferior to Prograf. Further studies are warranted to evaluate the long-term effect of graft function and tolerability.
REFERENCES  A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group. N Engl J Med 1994;331:1110e57.  Spence MM, Nguyen LM, Hui RL, Chan J. Evaluation of clinical and safety outcomes associated with conversion from brandname to generic tacrolimus in transplant recipients enrolled in an integrated health care system. Pharmacotherapy 2012;32:981e7.