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Efficacy and Safety of Generic Mycophenolate Mofetil (My-rept) 500-Milligram Tablets in Primary Liver Transplant Recipients
Efficacy and Safety of Generic Mycophenolate Mofetil (My-rept) 500-Milligram Tablets in Primary Liver Transplant Recipients S.K. Hong, K.-W. Lee*, K.C. Yoon, H.-S. Kim, H. Kim, N.-J. Yi, and K.-S. Suh Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
ABSTRACT Background. Generic immunosuppressants may be cost-effective if clinical outcomes are equivalent to the brand-name medications. Mycophenolate mofetil in the form of My-rept may be cost-effective being a generic immunosuppressant, which is available as a 500-mg tablet as well as a 250-mg capsule (Chong Kun Dang Pharmaceutical Corporation, Seoul, Korea). Objective. This study aimed to evaluate the efficacy, safety, cost-effectiveness, and convenience of My-rept 500-mg tablets in liver transplant recipients. Setting. The setting was an outpatient liver transplantation clinic of a tertiary hospital in Korea. Method. A phase 4, single-center, open-label, noncomparative study was undertaken. A total of 50 patients were recruited. Acute transplant rejection, changes in blood chemistry, white blood cell count, assessments of renal function, occurrence of adverse drug reactions, and other characteristics of the patients were recorded for 24 weeks. After study termination, a satisfaction survey was conducted. Results. All enrolled patients and their liver grafts had survived for 24 weeks posttransplantation. No episodes of acute rejection were reported. Nine patients (18.8%) presented with adverse drug reactions that had been commonly reported with the use of other mycophenolate mofetil products, and no serious adverse drug reactions were reported. Conclusion. In conclusion, the My-rept 500-mg tablet appears to be feasible and convenient for administration to recipients of a liver transplant.
C
ALCINEURIN inhibitors (CNIs) have been used as immunosuppressants after liver transplantation (LT) [1]. However, CNI use is associated with side effects such as nephrotoxicity, neurotoxicity, and glucose intolerance. Nephrotoxicity can induce long-term damage in the kidney and may lead to a poor long-term prognosis in patients who have undergone LT, another nonrenal organ transplantation, or a kidney transplantation [2]. Mycophenolate mofetil (MMF) is the most common auxiliary immunosuppressant used to relieve CNI-related complications [3]. Although MMF is widely used and is an effective auxiliary immunosuppressant in combination with CNIs, some problems of this treatment regimen have been identified. First, MMF use is associated with gastrointestinal complications such as nausea, vomiting, diarrhea, and
abdominal pain. These complications rarely appear in a serious form such as an ulcer or perforation. However, due to their relatively high frequency, gastrointestinal side effects may diminish the quality of life of transplant recipients. The development of leukopenia is another common complication that often requires patients to reduce the MMF dose [3,4].
0041-1345/17 http://dx.doi.org/10.1016/j.transproceed.2017.02.056
ª 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 230 Park Avenue, New York, NY 10169
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This open-label, single-center, noncomparative study (NESTea CSR, m317LTP11J) was sponsored by a grant from Chong Kun Dang Pharmaceutical Corporation, Korea. *Address correspondence to Kwang-Woong Lee, MD, Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. E-mail: [email protected]
Transplantation Proceedings, 49, 1402e1408 (2017)
EFFICACY AND SAFETY OF GENERIC MMF
Cellcept (Roche Pharmaceutical Corporation, Basel, Switzerland) is the original formulation of MMF. Several MMF generic products are available. My-rept, a 250-mg capsule produced by Chong Kun Dang Pharmaceutical Corporation (Seoul, Korea), was first introduced and approved by the Korean Food and Drug Administration (KFDA) in 2008. After comparing the pharmacokinetic profiles of the Cellcept 250-mg capsule and the My-rept 250-mg capsule, the KFDA stated that the two products were bioequivalent according to the KFDA-assigned range (90% confidence interval within 80% to 125% for relative
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mean maximum blood concentration [Cmax] and area under the plasma concentration-versus-time curve [AUC; 0et] or AUC [0eN]; Fig 1A). Clinical experience and research data also demonstrated that the 250-mg My-rept capsule was comparable with the 250-mg Cellcept capsule in terms of efficacy, lack of adverse events (AEs), and acceptable safety findings [5]. Only one Cellcept product is currently available in the Korean commercial market. However, My-rept is available as a 500-mg tablet as well as a 250-mg capsule. The My-rept 500-mg tablet was approved by the KFDA and was
Fig 1. Pharmacokinetic equivalence (based on a study from the Chong Kun Dang Pharmaceutical Corporation, Korea): (A) My-rept (four 250-mg capsules) vs Cellcept (four 250-mg capsules), (B) My-rept (two 500-mg tablets) vs Cellcept (four 250-mg capsules).
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Fig 2. Overview of study design.
produced starting in August 2010. It was considered bioequivalent according to KFDA rulings (Fig 1B), but no clinical studies have been conducted to assess the feasibility of this generic product. Therefore, in the current study, we evaluated the efficacy and safety of the 500-mg My-rept tablet in patients who had recently undergone LT. MATERIALS AND METHODS Study Design
Overview of the Study Design. This study was approved by the Seoul National University Hospital’s Institutional Review Board (approval number 1104-058-358). The overview of the study design is summarized in Fig 2. This single-center, open-label, noncomparative, phase 4 clinical trial was conducted to evaluate the efficacy and safety of the 500-mg My-rept tablet combined with tacrolimus administration for 24 weeks in primary LT patients. The number of subjects was not determined based on statistical calculations because this was an explorative study. Considering the number of LTs in 24 months at the medical center, we anticipated recruiting 50 subjects for the trial. Inclusion and Exclusion Criteria. Patients aged 19 to 65 years who were planning to receive a primary liver transplant from a deceased or living donor were included in the study. Patients who had previously undergone a LT within 72 hours were also eligible. Patients were required to be ABO identical or compatible. Women of childbearing age were required to present a negative urine or serum pregnancy test and agreed to use contraception during the study period. Patients who were multi-organ recipients or had previously undergone LT or another organ transplantation were excluded. Recipients or donors who were positive for human immunodeficiency virus (HIV) were also excluded. Additional exclusion criteria consisted of malignancy other than hepatocellular carcinoma within 5 years or after LT, major vascular invasion or extrahepatic metastasis of hepatocellular carcinoma, leukopenia (<2000 cells/mm3), absolute neutrophil count <900 cells/mm3, serum creatinine level of >2.0 mg/dL, and presence of a severe digestive disorder or a severe systemic infection. Women who were pregnant or lactating were also excluded.
Monitoring and Investigation of Safety and Efficacy. After initial monitoring on the day of the operation, patients were subjected to 10 more monitoring days (postoperative days 2, 7, 14, 28, 42, 56, 84, 112, 140, and 168). Acceptable variations in the monitoring schedule included a 1 day window for postoperative day 2, 3 days for postoperative days 7 and 14, 7 days for a postoperative duration of 4 weeks, and 14 days for a postoperative period of 12 weeks. Regular follow-up appointments were provided by hospitalization or outpatient follow-up, and follow-up monitoring including a physical examination, measurement of vital signs, determination of the trough level of blood tacrolimus, pharmacokinetic analysis of mycophenolic acid, complete laboratory assessment, administration of concomitant medication, and occurrence of AEs. Acute cellular rejection (ACR) was diagnosed through a liver biopsy. ACR was defined in patients with a score of 4 or higher on the rejection activity index assessment (RAI; Banff score: 0e2, no rejection; 3, borderline; 4e5, mild rejection; 6e7, moderate rejection; and 8e9, severe rejection) [6]. The primary endpoint of efficacy was the rate of ACR during 24 weeks of 500-mg My-rept tablet administration after LT. Other assessments included the onset and severity of ACR, patient survival rate, graft survival rate, renal function based on the estimated glomerular filtration rate (eGFR) and serum creatinine level, and comparison of drug serum concentrations based on the presence of ACR. The evaluation of safety criteria included the rate, type, and severity of any AEs. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Physical examinations, vital signs, routine laboratory tests, and concomitant medications were evaluated at every follow-up appointment. The incidence of hyperglycemia and hypertension requiring medication within 24 weeks after surgery, the incidence of leukopenia (<2000 cells/mm3) or thrombocytopenia (<30,000 cells/mm3), and the presence of an infection that required clinical treatment were also analyzed. Immunosuppressant Administration. All participants received intravenous basiliximab (within 2 hours of the LT procedure and on postoperative day 4 as induction therapy), tacrolimus (as the primary basal immunosuppressant), 500-mg My-rept tablets,
EFFICACY AND SAFETY OF GENERIC MMF
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and steroids. My-rept 500-mg tablets were administered within 72 hours of LT. A total daily dose of 1000 mg was administered in two divided doses every 12 hours. Dose adjustments based on blood levels were not conducted. The dose of My-rept could be reduced or treatment could be stopped if and when AEs were reported. The investigators determined that the dose of My-rept should not be reduced unless leukopenia occurred (<2000 cells/mm3) or the absolute neutrophil count decreased to <900 cells/mm3. However, if the medication was discontinued for more than 14 consecutive days, the subjects were excluded from the study. Tacrolimus treatment was initiated within 7 days after LT and was administered twice per day, every 12 hours. The initiation of medication administration depended on the condition of the patient. The tacrolimus dose during the initial 7 days after LT was 0.05e0.1 mg/kg/d according to individual clinical need, and the whole blood trough level of tacrolimus was 6e20 ng/mL for the first month, followed by 3e15 ng/mL until 6 months after LT, which was the end of the trial period. The medication dose could be reduced or treatment could be temporarily discontinued if AEs occurred, based on the recommendations of the investigators. However, if the medication was discontinued for more than 7 consecutive days, subjects were no longer eligible to participate in the study. Steroids were administered in the form of intravenous methylprednisolone (500e1000 mg) on the operative day, and patients were transitioned to oral prednisolone or medication was discontinued as recommended by the investigator.
SATISFACTION SURVEY
In this clinical trial, patients were administered one 500-mg tablet of My-rept twice per day during the trial period. After completion of the clinical trial, patients were converted to four 250-mg capsules of My-rept instead of two 500-mg tablets of My-rept. After a minimum of 4 weeks on the new medication regimen, an additional survey was conducted to assess patient satisfaction. The survey was administered during the hospital visit or over the phone. PATIENT ENROLLMENT
From August 2011 to May 2013, 48 primary LT patients were enrolled. Written informed consent was obtained from each participant prior to the study commencement.
STATISTICAL ANALYSIS
The efficacy evaluations targeted patients who met the inclusion/exclusion criteria and received at least one dose of study medication. Additional analyses targeted patients who met all of the main provisions of the study and terminated the study. The safety evaluations included patients who received at least one dose of study medication and underwent at least one safety assessment. Continuous variables are presented as means, medians, standard deviations, minimum values, and maximum values. Categorical parameters are presented as numbers of cases with the percentage in parentheses. Patient survival rates and graft survival rates were estimated using the Kaplan-Meier method. RESULTS Patients
This study was conducted from August 2011 to May 2013. Among the 50 patients providing written informed consent, 2 patients discontinued the study during the screening stage, and a total of 48 patients were enrolled. Of the 48 enrolled patients, 2 discontinued due to violations in selection criteria, 2 discontinued due to the occurrence of AEs (abdominal pain, leukopenia), 2 patients were excluded due to the withdrawal of consent, and 3 patients discontinued due to a change in immunosuppressant medication. Fortyone patients (85.4%) were male and seven patients (14.6%) were female. The median age was 55 years (range, 21e70 years). Hepatitis B viruserelated cirrhosis was the most common indication for LT (70.8%), followed by alcoholic cirrhosis (14.6%). Thirty patients (62.5%) had hepatocellular carcinoma (62.5%). The mean model for end-stage liver disease (MELD) score was 12.0 6.5 and the median was 9.0 (6.0e28.5). Liver tissue donation from a living relative was the most common characteristic of donors (79.2%), followed by donation from a living unrelated donor (16.7%) and tissue obtained from a deceased donor (4.2%; Table 1). Figure 3 shows a schematic graph of actual mean and median trough levels of tacrolimus during 24 weeks of treatment.
Table 1. Patient Demographics Recipient
Total Gender Age (y)
Blood type
n (%)
Male Female 20e40 40e60 >60 Mean SD Median (range) A B AB O
48 41 7 3
(100%) (85.4%) (14.6%) (6.2%)
38 (79.2%) 7 (14.6%) 53.42 8.08 55 (21e70) 19 (39.6%) 15 (31.2%) 5 (10.4%) 9 (18.8%)
Donor
Total Gender Age (y)
Donor type
Male Female <19 20e40 40e60 >60 Mean SD Median (range) Living related Living unrelated Deceased/cadaveric
n (%)
48 (100%) 34 (70.8%) 14 (29.2%) 2 (4.2%) 34 (70.8%) 11 (22.9%) 1 (2.1%) 32.9 12.9 29 (17e75) 38 (79.2%) 8 (16.6%) 2 (4.2%)
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Fig 3. A graph showing trough levels of tacrolimus during 24 weeks.
Efficacy and Safety
No patient mortality or cases of graft loss were observed, and no incidents of ACR were detected in biopsy specimens. The eGFR and serum creatinine levels were compared before and after administration of the study drug. The eGFR after 24 weeks was lower than the baseline eGFR (85.2 23.7 mL/min/1.73 m2 vs 119.6 76.5 mL/ min/1.73 m2; P ¼ .0009), and the serum creatinine concentration after 24 weeks was higher than that at baseline (0.8 0.3 mg/dL vs 1.0 0.3 mg/dL; P < .0001). Among the 48 enrolled patients, 39 patients (81.3%) reported experiencing more than one AE. Gastrointestinal events were the most common AE and occurred in 17 patients (35.4%); systemic events were reported in 14 patients (29.2%); respiratory events occurred in 13 patients (27.1%), and metabolic and nutritional events were reported in 8 patients (16.7%). Serious AEs were evaluated in 10 patients (20.8%) and included hepatobiliary events in 4 patients (8.3%), gastrointestinal events in 3 patients (6.3%), secondary term events (postoperative hematoma, postoperative intervention) in 3 patients (6.3%), and systemic events in 2 patients (4.2%). All AEs, except in 2 cases (benign prostatic hyperplasia and intracranial hemorrhage), were treated without any complications. Table 2. Details of ADRs System Organ Class
Hematologic disorder Leukopenia Neutropenia Thrombocytopenia Gastrointestinal disorder Abdominal pain Vomiting Diarrhea Nausea Hepatobiliary disorder LFT elevation Total
No. of Patients (%)
4 3 1 1 4 2 1 1 1 1 1 9
(8.3%) (6.3%) (2.1%) (2.1%) (8.3%) (4.2%) (2.1%) (2.1%) (2.1%) (2.1%) (2.1%) (100.0%)
Events
7 5 1 1 5 2 1 1 1 3 3 15
Note: Because duplicates are present for each of the criteria, the sum of the number of patients in each criterion is larger than the total number of patients.
Nine patients (18.8%) reported study medication-related adverse drug reactions (ADRs). Hematologic events occurred in four patients (8.3%), gastrointestinal events including abdominal pain, vomiting, diarrhea, and nausea were reported in four patients (8.3%), and abnormalities in liver function tests (LFTs) were detected in one patient (2.1%; Table 2). All of these ADRs were treated and resolved without any complications. No serious ADRs were reported. In terms of the items analyzed separately, infection requiring clinical treatment occurred in six patients (12.5%). Other safety-related events included hyperglycemia requiring medication after 24 weeks (8.3%), hypertension requiring medication after 24 weeks (4.2%), leukopenia (<2,000/mm3; 6.3%), and thrombocytopenia (<30,000/mm3; 2.1%). During the study, researchers were able to monitor and adjust the dose of the study medication within the acceptable range as described in the study protocol. The dose of My-rept tended to increase with time, but no statistically significant differences were observed for the medication dose. The mean medication dose at each visit is presented in Table 3. Among the 48 patients, 13 patients (27.1%) required a medication dose change (readministration after suspension, dose reduction, or discontinuation). A detailed list of patients who required adjustments in the dose of the study medication is summarized in Table 4. All participants were administered digestive drugs, antiulcer medications, and anti-infectives. Forty-seven patients (97.9%) were administered respiratory drugs, including medications to treat the common cold, and 27 patients (56.3%) were administered cardiovascular drugs, including antihypertensive drugs. Systolic and diastolic blood pressure values after 24 weeks of study drug administration were elevated compared with blood pressure values prior to medication administration; however, these values remained within the normal range (systolic blood pressure, 117.3 13.3 vs 122.0 8.4, P ¼ .025; diastolic blood pressure, 70.9 7.4 vs 75.4 6.2, P ¼ .001). No differences were detected in the pulse rate or body temperature of the study participants. After the termination of study, patient medication regimens were converted from two 500-mg tablets of My-rept to four 250-mg capsules of My-rept. Thirty of 48 patients completed the survey at a minimum of 4 weeks after conversion. Among these 30 patients, 27 (90.0%) stated that taking two tablets of 500-mg My-rept was more comfortable than taking four capsules of 250-mg My-rept. The other 3 patients (10.0%) observed no difference between the two dosing regimens. DISCUSSION
This study was a single-center, open-label, noncomparative, phase 4 clinical trial evaluating the efficacy and safety of 500-mg My-rept tablets in primary LT patients. The major criterion used to evaluate efficacy was the rate of ACR detected via biopsy within 24 weeks after LT. In this study, no cases of ACR were detected. All biopsies except one were performed for protocol biopsy. In one case, the biopsy
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Table 3. Mean Daily Dosage of My-rept Mean SD (mg)
No. of Patients (%)
My-rept Visit 2 (wk 0) Visit 3 (wk 1) Visit 4 (wk 2) Visit 5 (wk 4) Visit 6 (wk 6) Visit 7 (wk 8) Visit 8 (wk 12) Visit 9 (wk 16) Visit 10 (wk 20) Visit 11 (wk 24) Tacrolimus Visit 1 (wk 1) Visit 2 (wk 0) Visit 3 (wk 1) Visit 4 (wk 2) Visit 5 (w 4) Visit 6 (wk 6) Visit 7 (wk 8) Visit 8 (wk 12) Visit 9 (wk 16) Visit 10 (wk 20) Visit 11 (wk 24)
48 48 44 43 42 40 40 39 39 39
(100%) (100%) (91.7%) (89.6%) (87.5%) (83.3%) (83.3%) (81.3%) (81.3%) (81.3%)
708.3 937.5 988.6 976.7 976.2 1000.0 1000.0 1000.0 1000.0 1000.0
249.1 167.1 75.4 152.5 107.8 0.0 0.0 0.0 0.0 0.0
29 47 47 44 43 42 41 40 39 39 39
(60.4%) (97.9%) (97.9%) (91.7%) (89.6%) (87.5%) (85.4%) (83.3%) (81.3%) (81.3%) (81.3%)
0.7 1.2 3.1 4.9 4.9 5.0 5.0 4.8 4.4 4.1 4.0
0.4 0.6 1.0 1.8 1.9 2.0 1.8 1.9 1.8 1.6 1.7
was performed due to abnormal LFTs but proved to not be ACR. We previously reported the biopsy-proven ACR within the first year after LT as 2.7% for 74 recipients of living donor liver transplantation performed between 2009 and 2011 [7]. Despite the limitations of different characteristics of the cohort including type of LT and period, the results of the present study are encouraging.
The other criteria included the rate, period, and severity of ACR, patient survival, graft survival, kidney function based on the eGFR and serum creatinine level, and blood level of the drug as affected by ACR. Other criteria associated with ACR were not evaluated because no cases of ACR were detected in this study. All of the patients and grafts survived. The eGFR was decreased and the serum creatinine level was increased after 24 weeks of study medication administration, and the changes were statistically significant. However, no AEs related to the kidney or urinary tract were reported. The serum creatinine levels and urine analysis results were all within clinically normal ranges. Furthermore, no abnormal urogenital findings were observed during physical examinations. We can therefore conclude that overt renal dysfunction was not associated with administration of the 500-mg My-rept tablet. Considering the efficacy evaluations, the possibility of ACR would be expected to be very low given the high overall survival rate and the graft survival rate. Kidney function was unaffected by My-rept 500-mg treatment. Administration of the 500-mg My-rept tablet to LT recipients resulted in a similar safety profile to that reported in a study describing 15 ADRs in nine patients (18.8%), most of which were attributed to the same drug [8e10]. No patient deaths occurred, and all AEs, except two (benign prostatic hyperplasia and intracranial hemorrhage), were treated without complications. According to other studies, the incidence of at least one MMF dose reduction due to AEs ranges from 42.0%e70.3% with a standard dose of MMF, which is reported as either 2.0 or 3.0 g/d in renal transplant recipients [11e13]. MMF dose reduction is necessary in 25.0% to 35.0% of LT patients receiving MMF at a dose of 2.0 or 3.0 g/d due to side effects [8e10], and
Table 4. Detailed List of Dosage Changes Screening Number
AE
Readministration after suspension S03 Leukopenia S03 Thrombocytopenia S07 Abdominal pain S08 Wound dehiscence S15 LFT elevation S16 Biliary tract disorder S16 Fever S16 Abdominal pain S20 Nausea S20 Vomiting S29 Leukopenia S32 Diarrhea S37 Leukopenia S42 Seeding nodule Discontinuation S10 Hyperglycemia S33 Abdominal pain S37 Leukopenia Dose reduction S14 Neutropenia
Result
Relationship With the Study Medication
AE Grade
Serious AE
Moderate Moderate Mild Mild Mild Mild Mild Mild Mild Mild Mild Mild Mild Severe
No No No Yes No Yes No No No No No No No Yes
Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely
treated treated treated treated treated treated treated treated treated treated treated treated treated treated
Possible Possible Possible No Possible No No No Possible Possible Possible Possible Possible No
Moderate Mild Mild
No No No
Proceeding Completely treated Completely treated
No Possible Possible
Mild
No
Completely treated
Possible
Reason for Dropout
Tacrolimus to cyclosporine Adverse effect Adverse effect
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33.8% of patients require a reduction in the dose of MMF to 1.0 g/d [7]. In the current study, only 27.1% of patients required a dose change. Twenty-seven patients who replied to the survey stated that they felt more comfortable taking two 500-mg tablets of My-rept than taking four 250-mg capsules of My-rept. This preference may be due to the number of pills and the pill size. The 500-mg My-rept tablet is smaller than the 250-mg My-rept capsule (17.1 7.1 6.5 mm vs 19.2 7.2 6.4 mm). The convenience of taking fewer pills is one factor that affects medication compliance [14]. The costs of MMF in the commercial market in Korea are as follows: Cellcept 250-mg capsules, US $0.8; My-rept 250-mg capsules, US $0.7; and My-rept 500-mg tablets, US $1.1 (all values were converted using the 2016 exchange rate). The costs for a 1000 mg dose according to dosage form are as follows: Cellcept 250-mg capsules, US $3.2; My-rept 250-mg capsules, US $2.9; and My-rept 500-mg tablets, US $2.2. Considering that long-term use of MMF is necessary, differences in cost can be significant. This study has several limitations. First, it is a noncomparative study and therefore does not include a control group. Second, our results may not be generalized because of relatively low MELD score with limited race and original disease spectrum. Third, the study population consisted of outpatients, except at the beginning of the study, so study medication compliance could not be strictly assessed. Last, the number of patients was small, and long-term follow-up data are lacking; this study evaluated patients for 24 weeks after LT. In conclusion, the bioequivalent 500-mg My-rept tablet is efficient, safe, cost-effective, and convenient for patients after LT. REFERENCES [1] Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931e40.
HONG, LEE, YOON ET AL [2] Braun N, Dette S, Viebahn R. Impairment of renal function following liver transplantation. Transplant Proc 2003;35:1458e60. [3] Pageaux GP, Rostaing L, Calmus Y, Duvoux C, Vanlemmens C, Hardgwissen J, et al. Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Liver Transpl 2006;12: 1755e60. [4] The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996;61:1029e37. [5] Kim JM, Kwon CH, Yun IJ, Lee K-W, Yu HC, Suh KS, et al. A multicenter experience with generic mycophenolate mofetil conversion in stable liver transplant recipients. Ann Surg Treat Res 2014;86:192e8. [6] Demetris AJ, Batts KP, Dhillon AP, Ferrell L, Fung J, Geller SA, et al. Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997;25:658e63. [7] Kim H, Yi NJ, Lee J, Kim J, Moon MR, Jeong J, et al. Safety of reduced dose of mycophenolate mofetil combined with tacrolimus in living-donor liver transplantation. Clin Mol Hepatol 2014;20:291e9. [8] Dumortier J, Guillaud O, Pittau G, Salandre J, Adham M, Scoazec JY, et al. Introduction of mycophenolate mofetil in maintenance liver transplant recipients: what can we expect? Results of a 10-year experience. Transplant Proc 2010;42:2602e6. [9] Pfitzmann R, Klupp J, Langrehr JM, Uhl M, Neuhaus R, Settmacher U, et al. Mycophenolate mofetil for immunosuppression after liver transplantation. Transplantation 2003;76:130e6. [10] Sollinger HW. Mycophenolates in transplantation. Clin Transplant 2004;18:485e92. [11] Knoll GA, MacDonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003;14: 2381e6. [12] Mourad M, Malaise J, Chaib Eddour D, De Meyer M, König J, Schepers R, et al. Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil. Clin Chem 2001;47: 88e94. [13] Pelletier RP, Akin B, Henry ML, Bumgardner GL, Elkhammas EA, Rajab A, et al. The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant 2003;17:200e5. [14] Lin J, Sklar GE, Oh VMS, Li SC. Factors affecting therapeutic compliance: a review from the patient’s perspective. Ther Clin Risk Manag 2008;4:269e86.
ABSTRACT Background. Generic immunosuppressants may be cost-effective if clinical outcomes are equivalent to the brand-name medications. Mycophenolate mofetil in the form of My-rept may be cost-effective being a generic immunosuppressant, which is available as a 500-mg tablet as well as a 250-mg capsule (Chong Kun Dang Pharmaceutical Corporation, Seoul, Korea). Objective. This study aimed to evaluate the efficacy, safety, cost-effectiveness, and convenience of My-rept 500-mg tablets in liver transplant recipients. Setting. The setting was an outpatient liver transplantation clinic of a tertiary hospital in Korea. Method. A phase 4, single-center, open-label, noncomparative study was undertaken. A total of 50 patients were recruited. Acute transplant rejection, changes in blood chemistry, white blood cell count, assessments of renal function, occurrence of adverse drug reactions, and other characteristics of the patients were recorded for 24 weeks. After study termination, a satisfaction survey was conducted. Results. All enrolled patients and their liver grafts had survived for 24 weeks posttransplantation. No episodes of acute rejection were reported. Nine patients (18.8%) presented with adverse drug reactions that had been commonly reported with the use of other mycophenolate mofetil products, and no serious adverse drug reactions were reported. Conclusion. In conclusion, the My-rept 500-mg tablet appears to be feasible and convenient for administration to recipients of a liver transplant.
C
ALCINEURIN inhibitors (CNIs) have been used as immunosuppressants after liver transplantation (LT) [1]. However, CNI use is associated with side effects such as nephrotoxicity, neurotoxicity, and glucose intolerance. Nephrotoxicity can induce long-term damage in the kidney and may lead to a poor long-term prognosis in patients who have undergone LT, another nonrenal organ transplantation, or a kidney transplantation [2]. Mycophenolate mofetil (MMF) is the most common auxiliary immunosuppressant used to relieve CNI-related complications [3]. Although MMF is widely used and is an effective auxiliary immunosuppressant in combination with CNIs, some problems of this treatment regimen have been identified. First, MMF use is associated with gastrointestinal complications such as nausea, vomiting, diarrhea, and
abdominal pain. These complications rarely appear in a serious form such as an ulcer or perforation. However, due to their relatively high frequency, gastrointestinal side effects may diminish the quality of life of transplant recipients. The development of leukopenia is another common complication that often requires patients to reduce the MMF dose [3,4].
0041-1345/17 http://dx.doi.org/10.1016/j.transproceed.2017.02.056
ª 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 230 Park Avenue, New York, NY 10169
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This open-label, single-center, noncomparative study (NESTea CSR, m317LTP11J) was sponsored by a grant from Chong Kun Dang Pharmaceutical Corporation, Korea. *Address correspondence to Kwang-Woong Lee, MD, Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. E-mail: [email protected]
Transplantation Proceedings, 49, 1402e1408 (2017)
EFFICACY AND SAFETY OF GENERIC MMF
Cellcept (Roche Pharmaceutical Corporation, Basel, Switzerland) is the original formulation of MMF. Several MMF generic products are available. My-rept, a 250-mg capsule produced by Chong Kun Dang Pharmaceutical Corporation (Seoul, Korea), was first introduced and approved by the Korean Food and Drug Administration (KFDA) in 2008. After comparing the pharmacokinetic profiles of the Cellcept 250-mg capsule and the My-rept 250-mg capsule, the KFDA stated that the two products were bioequivalent according to the KFDA-assigned range (90% confidence interval within 80% to 125% for relative
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mean maximum blood concentration [Cmax] and area under the plasma concentration-versus-time curve [AUC; 0et] or AUC [0eN]; Fig 1A). Clinical experience and research data also demonstrated that the 250-mg My-rept capsule was comparable with the 250-mg Cellcept capsule in terms of efficacy, lack of adverse events (AEs), and acceptable safety findings [5]. Only one Cellcept product is currently available in the Korean commercial market. However, My-rept is available as a 500-mg tablet as well as a 250-mg capsule. The My-rept 500-mg tablet was approved by the KFDA and was
Fig 1. Pharmacokinetic equivalence (based on a study from the Chong Kun Dang Pharmaceutical Corporation, Korea): (A) My-rept (four 250-mg capsules) vs Cellcept (four 250-mg capsules), (B) My-rept (two 500-mg tablets) vs Cellcept (four 250-mg capsules).
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Fig 2. Overview of study design.
produced starting in August 2010. It was considered bioequivalent according to KFDA rulings (Fig 1B), but no clinical studies have been conducted to assess the feasibility of this generic product. Therefore, in the current study, we evaluated the efficacy and safety of the 500-mg My-rept tablet in patients who had recently undergone LT. MATERIALS AND METHODS Study Design
Overview of the Study Design. This study was approved by the Seoul National University Hospital’s Institutional Review Board (approval number 1104-058-358). The overview of the study design is summarized in Fig 2. This single-center, open-label, noncomparative, phase 4 clinical trial was conducted to evaluate the efficacy and safety of the 500-mg My-rept tablet combined with tacrolimus administration for 24 weeks in primary LT patients. The number of subjects was not determined based on statistical calculations because this was an explorative study. Considering the number of LTs in 24 months at the medical center, we anticipated recruiting 50 subjects for the trial. Inclusion and Exclusion Criteria. Patients aged 19 to 65 years who were planning to receive a primary liver transplant from a deceased or living donor were included in the study. Patients who had previously undergone a LT within 72 hours were also eligible. Patients were required to be ABO identical or compatible. Women of childbearing age were required to present a negative urine or serum pregnancy test and agreed to use contraception during the study period. Patients who were multi-organ recipients or had previously undergone LT or another organ transplantation were excluded. Recipients or donors who were positive for human immunodeficiency virus (HIV) were also excluded. Additional exclusion criteria consisted of malignancy other than hepatocellular carcinoma within 5 years or after LT, major vascular invasion or extrahepatic metastasis of hepatocellular carcinoma, leukopenia (<2000 cells/mm3), absolute neutrophil count <900 cells/mm3, serum creatinine level of >2.0 mg/dL, and presence of a severe digestive disorder or a severe systemic infection. Women who were pregnant or lactating were also excluded.
Monitoring and Investigation of Safety and Efficacy. After initial monitoring on the day of the operation, patients were subjected to 10 more monitoring days (postoperative days 2, 7, 14, 28, 42, 56, 84, 112, 140, and 168). Acceptable variations in the monitoring schedule included a 1 day window for postoperative day 2, 3 days for postoperative days 7 and 14, 7 days for a postoperative duration of 4 weeks, and 14 days for a postoperative period of 12 weeks. Regular follow-up appointments were provided by hospitalization or outpatient follow-up, and follow-up monitoring including a physical examination, measurement of vital signs, determination of the trough level of blood tacrolimus, pharmacokinetic analysis of mycophenolic acid, complete laboratory assessment, administration of concomitant medication, and occurrence of AEs. Acute cellular rejection (ACR) was diagnosed through a liver biopsy. ACR was defined in patients with a score of 4 or higher on the rejection activity index assessment (RAI; Banff score: 0e2, no rejection; 3, borderline; 4e5, mild rejection; 6e7, moderate rejection; and 8e9, severe rejection) [6]. The primary endpoint of efficacy was the rate of ACR during 24 weeks of 500-mg My-rept tablet administration after LT. Other assessments included the onset and severity of ACR, patient survival rate, graft survival rate, renal function based on the estimated glomerular filtration rate (eGFR) and serum creatinine level, and comparison of drug serum concentrations based on the presence of ACR. The evaluation of safety criteria included the rate, type, and severity of any AEs. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Physical examinations, vital signs, routine laboratory tests, and concomitant medications were evaluated at every follow-up appointment. The incidence of hyperglycemia and hypertension requiring medication within 24 weeks after surgery, the incidence of leukopenia (<2000 cells/mm3) or thrombocytopenia (<30,000 cells/mm3), and the presence of an infection that required clinical treatment were also analyzed. Immunosuppressant Administration. All participants received intravenous basiliximab (within 2 hours of the LT procedure and on postoperative day 4 as induction therapy), tacrolimus (as the primary basal immunosuppressant), 500-mg My-rept tablets,
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and steroids. My-rept 500-mg tablets were administered within 72 hours of LT. A total daily dose of 1000 mg was administered in two divided doses every 12 hours. Dose adjustments based on blood levels were not conducted. The dose of My-rept could be reduced or treatment could be stopped if and when AEs were reported. The investigators determined that the dose of My-rept should not be reduced unless leukopenia occurred (<2000 cells/mm3) or the absolute neutrophil count decreased to <900 cells/mm3. However, if the medication was discontinued for more than 14 consecutive days, the subjects were excluded from the study. Tacrolimus treatment was initiated within 7 days after LT and was administered twice per day, every 12 hours. The initiation of medication administration depended on the condition of the patient. The tacrolimus dose during the initial 7 days after LT was 0.05e0.1 mg/kg/d according to individual clinical need, and the whole blood trough level of tacrolimus was 6e20 ng/mL for the first month, followed by 3e15 ng/mL until 6 months after LT, which was the end of the trial period. The medication dose could be reduced or treatment could be temporarily discontinued if AEs occurred, based on the recommendations of the investigators. However, if the medication was discontinued for more than 7 consecutive days, subjects were no longer eligible to participate in the study. Steroids were administered in the form of intravenous methylprednisolone (500e1000 mg) on the operative day, and patients were transitioned to oral prednisolone or medication was discontinued as recommended by the investigator.
SATISFACTION SURVEY
In this clinical trial, patients were administered one 500-mg tablet of My-rept twice per day during the trial period. After completion of the clinical trial, patients were converted to four 250-mg capsules of My-rept instead of two 500-mg tablets of My-rept. After a minimum of 4 weeks on the new medication regimen, an additional survey was conducted to assess patient satisfaction. The survey was administered during the hospital visit or over the phone. PATIENT ENROLLMENT
From August 2011 to May 2013, 48 primary LT patients were enrolled. Written informed consent was obtained from each participant prior to the study commencement.
STATISTICAL ANALYSIS
The efficacy evaluations targeted patients who met the inclusion/exclusion criteria and received at least one dose of study medication. Additional analyses targeted patients who met all of the main provisions of the study and terminated the study. The safety evaluations included patients who received at least one dose of study medication and underwent at least one safety assessment. Continuous variables are presented as means, medians, standard deviations, minimum values, and maximum values. Categorical parameters are presented as numbers of cases with the percentage in parentheses. Patient survival rates and graft survival rates were estimated using the Kaplan-Meier method. RESULTS Patients
This study was conducted from August 2011 to May 2013. Among the 50 patients providing written informed consent, 2 patients discontinued the study during the screening stage, and a total of 48 patients were enrolled. Of the 48 enrolled patients, 2 discontinued due to violations in selection criteria, 2 discontinued due to the occurrence of AEs (abdominal pain, leukopenia), 2 patients were excluded due to the withdrawal of consent, and 3 patients discontinued due to a change in immunosuppressant medication. Fortyone patients (85.4%) were male and seven patients (14.6%) were female. The median age was 55 years (range, 21e70 years). Hepatitis B viruserelated cirrhosis was the most common indication for LT (70.8%), followed by alcoholic cirrhosis (14.6%). Thirty patients (62.5%) had hepatocellular carcinoma (62.5%). The mean model for end-stage liver disease (MELD) score was 12.0 6.5 and the median was 9.0 (6.0e28.5). Liver tissue donation from a living relative was the most common characteristic of donors (79.2%), followed by donation from a living unrelated donor (16.7%) and tissue obtained from a deceased donor (4.2%; Table 1). Figure 3 shows a schematic graph of actual mean and median trough levels of tacrolimus during 24 weeks of treatment.
Table 1. Patient Demographics Recipient
Total Gender Age (y)
Blood type
n (%)
Male Female 20e40 40e60 >60 Mean SD Median (range) A B AB O
48 41 7 3
(100%) (85.4%) (14.6%) (6.2%)
38 (79.2%) 7 (14.6%) 53.42 8.08 55 (21e70) 19 (39.6%) 15 (31.2%) 5 (10.4%) 9 (18.8%)
Donor
Total Gender Age (y)
Donor type
Male Female <19 20e40 40e60 >60 Mean SD Median (range) Living related Living unrelated Deceased/cadaveric
n (%)
48 (100%) 34 (70.8%) 14 (29.2%) 2 (4.2%) 34 (70.8%) 11 (22.9%) 1 (2.1%) 32.9 12.9 29 (17e75) 38 (79.2%) 8 (16.6%) 2 (4.2%)
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Fig 3. A graph showing trough levels of tacrolimus during 24 weeks.
Efficacy and Safety
No patient mortality or cases of graft loss were observed, and no incidents of ACR were detected in biopsy specimens. The eGFR and serum creatinine levels were compared before and after administration of the study drug. The eGFR after 24 weeks was lower than the baseline eGFR (85.2 23.7 mL/min/1.73 m2 vs 119.6 76.5 mL/ min/1.73 m2; P ¼ .0009), and the serum creatinine concentration after 24 weeks was higher than that at baseline (0.8 0.3 mg/dL vs 1.0 0.3 mg/dL; P < .0001). Among the 48 enrolled patients, 39 patients (81.3%) reported experiencing more than one AE. Gastrointestinal events were the most common AE and occurred in 17 patients (35.4%); systemic events were reported in 14 patients (29.2%); respiratory events occurred in 13 patients (27.1%), and metabolic and nutritional events were reported in 8 patients (16.7%). Serious AEs were evaluated in 10 patients (20.8%) and included hepatobiliary events in 4 patients (8.3%), gastrointestinal events in 3 patients (6.3%), secondary term events (postoperative hematoma, postoperative intervention) in 3 patients (6.3%), and systemic events in 2 patients (4.2%). All AEs, except in 2 cases (benign prostatic hyperplasia and intracranial hemorrhage), were treated without any complications. Table 2. Details of ADRs System Organ Class
Hematologic disorder Leukopenia Neutropenia Thrombocytopenia Gastrointestinal disorder Abdominal pain Vomiting Diarrhea Nausea Hepatobiliary disorder LFT elevation Total
No. of Patients (%)
4 3 1 1 4 2 1 1 1 1 1 9
(8.3%) (6.3%) (2.1%) (2.1%) (8.3%) (4.2%) (2.1%) (2.1%) (2.1%) (2.1%) (2.1%) (100.0%)
Events
7 5 1 1 5 2 1 1 1 3 3 15
Note: Because duplicates are present for each of the criteria, the sum of the number of patients in each criterion is larger than the total number of patients.
Nine patients (18.8%) reported study medication-related adverse drug reactions (ADRs). Hematologic events occurred in four patients (8.3%), gastrointestinal events including abdominal pain, vomiting, diarrhea, and nausea were reported in four patients (8.3%), and abnormalities in liver function tests (LFTs) were detected in one patient (2.1%; Table 2). All of these ADRs were treated and resolved without any complications. No serious ADRs were reported. In terms of the items analyzed separately, infection requiring clinical treatment occurred in six patients (12.5%). Other safety-related events included hyperglycemia requiring medication after 24 weeks (8.3%), hypertension requiring medication after 24 weeks (4.2%), leukopenia (<2,000/mm3; 6.3%), and thrombocytopenia (<30,000/mm3; 2.1%). During the study, researchers were able to monitor and adjust the dose of the study medication within the acceptable range as described in the study protocol. The dose of My-rept tended to increase with time, but no statistically significant differences were observed for the medication dose. The mean medication dose at each visit is presented in Table 3. Among the 48 patients, 13 patients (27.1%) required a medication dose change (readministration after suspension, dose reduction, or discontinuation). A detailed list of patients who required adjustments in the dose of the study medication is summarized in Table 4. All participants were administered digestive drugs, antiulcer medications, and anti-infectives. Forty-seven patients (97.9%) were administered respiratory drugs, including medications to treat the common cold, and 27 patients (56.3%) were administered cardiovascular drugs, including antihypertensive drugs. Systolic and diastolic blood pressure values after 24 weeks of study drug administration were elevated compared with blood pressure values prior to medication administration; however, these values remained within the normal range (systolic blood pressure, 117.3 13.3 vs 122.0 8.4, P ¼ .025; diastolic blood pressure, 70.9 7.4 vs 75.4 6.2, P ¼ .001). No differences were detected in the pulse rate or body temperature of the study participants. After the termination of study, patient medication regimens were converted from two 500-mg tablets of My-rept to four 250-mg capsules of My-rept. Thirty of 48 patients completed the survey at a minimum of 4 weeks after conversion. Among these 30 patients, 27 (90.0%) stated that taking two tablets of 500-mg My-rept was more comfortable than taking four capsules of 250-mg My-rept. The other 3 patients (10.0%) observed no difference between the two dosing regimens. DISCUSSION
This study was a single-center, open-label, noncomparative, phase 4 clinical trial evaluating the efficacy and safety of 500-mg My-rept tablets in primary LT patients. The major criterion used to evaluate efficacy was the rate of ACR detected via biopsy within 24 weeks after LT. In this study, no cases of ACR were detected. All biopsies except one were performed for protocol biopsy. In one case, the biopsy
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Table 3. Mean Daily Dosage of My-rept Mean SD (mg)
No. of Patients (%)
My-rept Visit 2 (wk 0) Visit 3 (wk 1) Visit 4 (wk 2) Visit 5 (wk 4) Visit 6 (wk 6) Visit 7 (wk 8) Visit 8 (wk 12) Visit 9 (wk 16) Visit 10 (wk 20) Visit 11 (wk 24) Tacrolimus Visit 1 (wk 1) Visit 2 (wk 0) Visit 3 (wk 1) Visit 4 (wk 2) Visit 5 (w 4) Visit 6 (wk 6) Visit 7 (wk 8) Visit 8 (wk 12) Visit 9 (wk 16) Visit 10 (wk 20) Visit 11 (wk 24)
48 48 44 43 42 40 40 39 39 39
(100%) (100%) (91.7%) (89.6%) (87.5%) (83.3%) (83.3%) (81.3%) (81.3%) (81.3%)
708.3 937.5 988.6 976.7 976.2 1000.0 1000.0 1000.0 1000.0 1000.0
249.1 167.1 75.4 152.5 107.8 0.0 0.0 0.0 0.0 0.0
29 47 47 44 43 42 41 40 39 39 39
(60.4%) (97.9%) (97.9%) (91.7%) (89.6%) (87.5%) (85.4%) (83.3%) (81.3%) (81.3%) (81.3%)
0.7 1.2 3.1 4.9 4.9 5.0 5.0 4.8 4.4 4.1 4.0
0.4 0.6 1.0 1.8 1.9 2.0 1.8 1.9 1.8 1.6 1.7
was performed due to abnormal LFTs but proved to not be ACR. We previously reported the biopsy-proven ACR within the first year after LT as 2.7% for 74 recipients of living donor liver transplantation performed between 2009 and 2011 [7]. Despite the limitations of different characteristics of the cohort including type of LT and period, the results of the present study are encouraging.
The other criteria included the rate, period, and severity of ACR, patient survival, graft survival, kidney function based on the eGFR and serum creatinine level, and blood level of the drug as affected by ACR. Other criteria associated with ACR were not evaluated because no cases of ACR were detected in this study. All of the patients and grafts survived. The eGFR was decreased and the serum creatinine level was increased after 24 weeks of study medication administration, and the changes were statistically significant. However, no AEs related to the kidney or urinary tract were reported. The serum creatinine levels and urine analysis results were all within clinically normal ranges. Furthermore, no abnormal urogenital findings were observed during physical examinations. We can therefore conclude that overt renal dysfunction was not associated with administration of the 500-mg My-rept tablet. Considering the efficacy evaluations, the possibility of ACR would be expected to be very low given the high overall survival rate and the graft survival rate. Kidney function was unaffected by My-rept 500-mg treatment. Administration of the 500-mg My-rept tablet to LT recipients resulted in a similar safety profile to that reported in a study describing 15 ADRs in nine patients (18.8%), most of which were attributed to the same drug [8e10]. No patient deaths occurred, and all AEs, except two (benign prostatic hyperplasia and intracranial hemorrhage), were treated without complications. According to other studies, the incidence of at least one MMF dose reduction due to AEs ranges from 42.0%e70.3% with a standard dose of MMF, which is reported as either 2.0 or 3.0 g/d in renal transplant recipients [11e13]. MMF dose reduction is necessary in 25.0% to 35.0% of LT patients receiving MMF at a dose of 2.0 or 3.0 g/d due to side effects [8e10], and
Table 4. Detailed List of Dosage Changes Screening Number
AE
Readministration after suspension S03 Leukopenia S03 Thrombocytopenia S07 Abdominal pain S08 Wound dehiscence S15 LFT elevation S16 Biliary tract disorder S16 Fever S16 Abdominal pain S20 Nausea S20 Vomiting S29 Leukopenia S32 Diarrhea S37 Leukopenia S42 Seeding nodule Discontinuation S10 Hyperglycemia S33 Abdominal pain S37 Leukopenia Dose reduction S14 Neutropenia
Result
Relationship With the Study Medication
AE Grade
Serious AE
Moderate Moderate Mild Mild Mild Mild Mild Mild Mild Mild Mild Mild Mild Severe
No No No Yes No Yes No No No No No No No Yes
Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely Completely
treated treated treated treated treated treated treated treated treated treated treated treated treated treated
Possible Possible Possible No Possible No No No Possible Possible Possible Possible Possible No
Moderate Mild Mild
No No No
Proceeding Completely treated Completely treated
No Possible Possible
Mild
No
Completely treated
Possible
Reason for Dropout
Tacrolimus to cyclosporine Adverse effect Adverse effect
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33.8% of patients require a reduction in the dose of MMF to 1.0 g/d [7]. In the current study, only 27.1% of patients required a dose change. Twenty-seven patients who replied to the survey stated that they felt more comfortable taking two 500-mg tablets of My-rept than taking four 250-mg capsules of My-rept. This preference may be due to the number of pills and the pill size. The 500-mg My-rept tablet is smaller than the 250-mg My-rept capsule (17.1 7.1 6.5 mm vs 19.2 7.2 6.4 mm). The convenience of taking fewer pills is one factor that affects medication compliance [14]. The costs of MMF in the commercial market in Korea are as follows: Cellcept 250-mg capsules, US $0.8; My-rept 250-mg capsules, US $0.7; and My-rept 500-mg tablets, US $1.1 (all values were converted using the 2016 exchange rate). The costs for a 1000 mg dose according to dosage form are as follows: Cellcept 250-mg capsules, US $3.2; My-rept 250-mg capsules, US $2.9; and My-rept 500-mg tablets, US $2.2. Considering that long-term use of MMF is necessary, differences in cost can be significant. This study has several limitations. First, it is a noncomparative study and therefore does not include a control group. Second, our results may not be generalized because of relatively low MELD score with limited race and original disease spectrum. Third, the study population consisted of outpatients, except at the beginning of the study, so study medication compliance could not be strictly assessed. Last, the number of patients was small, and long-term follow-up data are lacking; this study evaluated patients for 24 weeks after LT. In conclusion, the bioequivalent 500-mg My-rept tablet is efficient, safe, cost-effective, and convenient for patients after LT. REFERENCES [1] Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931e40.
HONG, LEE, YOON ET AL [2] Braun N, Dette S, Viebahn R. Impairment of renal function following liver transplantation. Transplant Proc 2003;35:1458e60. [3] Pageaux GP, Rostaing L, Calmus Y, Duvoux C, Vanlemmens C, Hardgwissen J, et al. Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Liver Transpl 2006;12: 1755e60. [4] The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996;61:1029e37. [5] Kim JM, Kwon CH, Yun IJ, Lee K-W, Yu HC, Suh KS, et al. A multicenter experience with generic mycophenolate mofetil conversion in stable liver transplant recipients. Ann Surg Treat Res 2014;86:192e8. [6] Demetris AJ, Batts KP, Dhillon AP, Ferrell L, Fung J, Geller SA, et al. Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997;25:658e63. [7] Kim H, Yi NJ, Lee J, Kim J, Moon MR, Jeong J, et al. Safety of reduced dose of mycophenolate mofetil combined with tacrolimus in living-donor liver transplantation. Clin Mol Hepatol 2014;20:291e9. [8] Dumortier J, Guillaud O, Pittau G, Salandre J, Adham M, Scoazec JY, et al. Introduction of mycophenolate mofetil in maintenance liver transplant recipients: what can we expect? Results of a 10-year experience. Transplant Proc 2010;42:2602e6. [9] Pfitzmann R, Klupp J, Langrehr JM, Uhl M, Neuhaus R, Settmacher U, et al. Mycophenolate mofetil for immunosuppression after liver transplantation. Transplantation 2003;76:130e6. [10] Sollinger HW. Mycophenolates in transplantation. Clin Transplant 2004;18:485e92. [11] Knoll GA, MacDonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003;14: 2381e6. [12] Mourad M, Malaise J, Chaib Eddour D, De Meyer M, König J, Schepers R, et al. Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil. Clin Chem 2001;47: 88e94. [13] Pelletier RP, Akin B, Henry ML, Bumgardner GL, Elkhammas EA, Rajab A, et al. The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant 2003;17:200e5. [14] Lin J, Sklar GE, Oh VMS, Li SC. Factors affecting therapeutic compliance: a review from the patient’s perspective. Ther Clin Risk Manag 2008;4:269e86.