|Year : 2017 | Volume
| Issue : 2 | Page : 70-76
Immunosuppression with prolonged-release tacrolimus in kidney or liver transplantation in India
Dinesh Khullar1, Vikranth Reddy2, Budithi Subbarao3, Madan Bahadur4, Veeraswamy Tamilarasi5, Alan Almeida6, Pratik Shah7
1 Nephrology and Kidney Transplant Medicine, Sir Ganga Ram Hospital, New Delhi, Delhi, India
2 Department of Nephrology, Care Hospitals, Hyderabad, Telangana, India
3 Department of Nephrology, Apollo Hospitals, Chennai, India
4 Department of Nephrologyand Dialysis, Jaslok Hospital and Research Centre, Mumbai, Maharashtra, India
5 Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India
6 Department of Nephrology, P.D. Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra, India
7 Department of Medical and Development, Astellas Pharma Pvt Ltd., Mumbai, Maharashtra, India
|Date of Web Publication||12-Sep-2017|
Nephrology and Renal Transplant Medicine, Max Super Speciality Hospital, Saket, New Delhi - 110 017
Source of Support: None, Conflict of Interest: None
Aim: Tacrolimus has proven efficacy as an immunosuppressive therapy to prevent transplant rejection and is widely used as an immediate-release formulation in a twice-daily regimen. Once-daily prolonged-release tacrolimus aims to improve the outcomes by reducing variability in exposure and improving adherence. However, there are limited published data available on prolonged-release tacrolimus in routine clinical practice in India. Methods: This was a Phase IV, multicenter, prospective study of prolonged-release tacrolimus conducted over 12 weeks in adult patients eligible for de novo kidney or liver transplantation in India. Primary efficacy end-point was the event rate of biopsy-confirmed acute rejections (BCARs). Secondary end-points included corticosteroid-resistant rejection incidence, time to first BCAR, graft loss, and death. Safety end-points included renal function, lipid profile, incidence of new-onset diabetes mellitus after transplantation (NODAT), and infection. Results: The study enrolled 92 patients undergoing kidney (81 [88.0%]) or liver transplantation (11 [12.0%]); a total of 76 patients (82.6%) completed the study. Ten kidney transplant patients (overall 10.9%) experienced BCAR. There were seven corticosteroid-sensitive and three corticosteroid-resistant rejections. Median (range) time to kidney transplant rejection was 6.5 (1.0–76.0) days. Renal function was stable or improved. Lipid levels showed a significant increase. Eleven instances of NODAT and seven infections occurred and there were eight deaths (8.7%; six kidney and two liver transplant patients). Conclusions: In de novo kidney and liver transplant recipients in India, prolonged-release tacrolimus was well-tolerated and efficacious with a low incidence of acute rejection. Safety profile was similar to immediate-release tacrolimus from published data.
Keywords: Acute rejection, calcineurin inhibitor, immunosuppressive therapy, transplant
|How to cite this article:|
Khullar D, Reddy V, Subbarao B, Bahadur M, Tamilarasi V, Almeida A, Shah P. Immunosuppression with prolonged-release tacrolimus in kidney or liver transplantation in India. Indian J Transplant 2017;11:70-6
|How to cite this URL:|
Khullar D, Reddy V, Subbarao B, Bahadur M, Tamilarasi V, Almeida A, Shah P. Immunosuppression with prolonged-release tacrolimus in kidney or liver transplantation in India. Indian J Transplant [serial online] 2017 [cited 2019 Sep 22];11:70-6. Available from: http://www.ijtonline.in/text.asp?2017/11/2/70/214382
| Introduction|| |
Effective immunosuppressive therapy is key to successful outcomes in patients undergoing organ transplantation. The goal of immunosuppressive therapy is to maintain the graft function with a low rate of acute graft rejection and to minimize adverse events (AEs), ensuring the optimal balance between under- and over-immunosuppression. Calcineurin inhibitors, such as cyclosporine A and tacrolimus, and antiproliferative agents, such as mycophenolate mofetil, are key components in immunosuppressive treatment regimens.,
Tacrolimus has proven efficacy as an immunosuppressive therapy in kidney and liver transplantation when used in a twice-daily immediate-release regimen and has shown reduced acute rejection and better graft survival compared with cyclosporine A., Despite its proven efficacy, twice-daily dosing schedules have been associated with nonadherence that may contribute to rejection episodes and graft loss. Furthermore, reduced renal allograft survival has been observed in patients with higher variability in tacrolimus trough-levels. Therefore, once-daily prolonged-release tacrolimus was developed with the aim of further improving outcomes by reducing variability in exposure and improving adherence (for a recent review see Posadas Salas and Srinivas 2014)., Clinical trials have shown that once-daily treatment with prolonged-release tacrolimus is noninferior to treatment with the same dose of twice-daily immediate-release tacrolimus,,,,, with European Liver Transplant Registry results showing significant improvements in long-term outcomes in liver transplant patients treated with this formulation compared with those receiving immediate-release tacrolimus. Prolonged-release tacrolimus is widely used in clinical practice in Europe,, but there are limited published data available in patients undergoing transplantation in India. A recent Indian study assessed tacrolimus-related AEs and their relationship with trough levels in liver transplant patients  and single-center experiences with tacrolimus in India have been reported; however, studies across different transplant types with large patient numbers are still lacking. This study aims to address this need by assessing the efficacy and safety of prolonged-release tacrolimus in liver and kidney transplantation patients in India.
| Methods|| |
This study was a Phase IV, multicenter, prospective study of prolonged-release tacrolimus (Advagraf ®, Astellas Pharma Inc., [2-5-1, Nihonbashi-Honcho, Chuo-Ku, Tokyo 103-8411, Japan], hereafter defined as prolonged-release tacrolimus) in adult patients undergoing kidney or liver transplantation in centers in India (trial number: CTRI/2012/01/002361). The trial was conducted over 12 weeks, during which patients had nine visits (baseline [day 0], day 1, day 3 ± 1, day 7 ± 1, day 11 ± 1, day 14 ± 1, day 28 ± 1, day 56 ± 3, and day 84 ± 5 [end of the study]). All visits were scheduled from the date of reperfusion (day 0) with screening visits performed up to 14 days before surgery.
The study was performed in compliance with guidelines for clinical trials on pharmaceutical products in India. Written informed consent was obtained from all patients. Ethics committee approval was received for respective sites before study initiation.
Adult patients, aged 18–65 years, undergoing de novo liver or kidney transplant from a cadaveric or living donor were enrolled in the study. The exclusion criteria included patients scheduled for transplants other than liver or kidney, patients with malignancy or a history of malignancy within the past 5 years, patients with systemic infection requiring treatment, patients with severe diarrhea, active peptic ulcer, or patients with a gastrointestinal disorder that may affect tacrolimus absorption. Kidney transplant patients were also excluded if the cold ischemia time of the donor kidney was >30 h, if there was a high immunologic risk (positive crossmatch or panel reactive antibody grade >50% in the past 6 months), if liver cirrhosis or significant liver disease was present, or if the patient was known to be hepatitis B or C positive. Liver transplant patients were excluded if serum creatinine levels were >2 mg/dl or if the patient was transplanted for hepatocellular carcinoma with a single nodule >5 cm in diameter, >3 nodules, or metastases or vascular tumor invasion.
Patients received prolonged-release tacrolimus administered orally as one dose in the morning, in conjunction with other immunosuppressive agents in the initial postoperative period. The initial dose of prolonged-release tacrolimus for kidney transplant patients was 0.2 mg/kg/day. Administration was commenced before surgery or within 24 h after surgery completion. For liver transplant patients, the initial tacrolimus dose was 0.1–0.2 mg/kg/day, and administration was commenced within 18 h postsurgery. The study did not contain a control arm.
Modifications of tacrolimus dose were permitted, as considered necessary by the investigators, according to clinical signs and tacrolimus whole blood trough concentrations. Concomitant medications allowed during the study were methylprednisolone (or equivalent), oral prednisolone (or equivalent), mycophenolate mofetil, or antibody induction therapy. Concomitant medications not allowed during the study were azathioprine, rapamycin, or cyclosporine.
Primary and secondary efficacy outcomes
The primary efficacy end-point was the event rate of biopsy-confirmed acute rejections (BCARs). If there were clinical and/or laboratory signs that indicated a rejection episode, a kidney or liver biopsy was performed. For kidney transplant patients, the primary efficacy end-point was defined as BCAR ≥ Grade 1 (according to Banff 2007 working classification of renal allograft pathology ), within the first 12 weeks of transplantation. For liver transplant patients, the primary efficacy end-point was defined as BCAR with a rejection activity index of ≥4 (defined according to the 1997 Banff schema for grading liver allograft rejection ) within the first 12 weeks of transplantation. Secondary efficacy end-points included time to first BCAR, overall frequency of acute rejection episodes, severity of BCAR, incidence of corticosteroid-resistant and corticosteroid-sensitive rejections, graft loss, and death. Graft loss or failure was defined as re-transplantation, death, nephrectomy, or as dialysis ongoing at the end of study for kidney transplant patients.
Tacrolimus blood levels
Tacrolimus whole blood trough levels were monitored using liquid chromatography–mass spectrometry analysis. Target tacrolimus trough levels for kidney transplant patients from day 1 to day 14 was 8–15 ng/ml and from day 15 to week 12, it was 5–12 ng/ml. Target level for liver transplant patients from day 1 to day 14 was 5–15 ng/ml and from day 15 to week 12, it was 4–10 ng/ml. Blood samples were taken in the morning before tacrolimus administration on days 3, 7, 11, 14, 21, 28, 42, 56, and 84. Patients who were treated with prolonged-release tacrolimus before kidney transplantation had their first whole blood tacrolimus trough levels monitored on day 1.
Safety and laboratory assessments
The primary safety end-points were renal function as assessed by serum creatinine levels, lipid profile, incidence of infection, and incidence of new-onset diabetes mellitus after transplantation (NODAT; defined as the first occurrence of one of the following four parameters: Two fasting glucose levels >126 mg/dl that were >30 days apart; oral hypoglycemic agent use for >30 consecutive days; insulin therapy for >30 consecutive days; and HbA1c >6.5%). AEs were evaluated during the study. Laboratory assessments included complete blood counts, renal and lipid profile, and fasting blood glucose. Lipid levels were assessed at baseline, day 28, and day 84. Electrocardiograms were performed at screening, day 28, and day 84.
Tacrolimus whole blood trough levels were used as a rough guide to assess patient adherence. In addition, the number of capsules of the returned treatment was counted, and treatment adherence was calculated.
No formal hypothesis was being tested; a total of 200 kidney or liver transplant patients meeting all eligibility criteria were planned for inclusion in the recruitment period of 1 year.
All safety and efficacy parameters were summarized using descriptive statistics (categorical variables: Number, percentage; continuous variables: Mean, standard deviation (SD), median, minimum and maximum). For all quantitative laboratory parameters, actual value and change from baseline to end of the treatment were summarized descriptively. SAS 9.2 (or a later version; SAS, Cary, USA) was used to perform the statistical analyses.
| Results|| |
The trial began on March 21, 2012 and ended on May 14, 2013. A total of 101 patients were screened for inclusion, of which 92 patients were enrolled into the study [Supplementary Figure 1] [Additional file 1]. Overall, 76 patients (82.6%) were alive at week 12 and eight patients died (8.7%), of whom six were kidney transplant patients and two were liver transplant patients. Seventy-six patients deviated from the protocol (minor deviation for viral serology; Epstein–Barr virus was not performed for the donor). Eight patients (8.7%) discontinued the study; three patients due to AEs (3.3%; thrombotic microangiopathy, acute renal cortical necrosis, and acute renal failure), three patients due to patient decision (3.3%), and two patients due to physician decision (2.2%). One patient who was enrolled, but discontinued the trial, did not take the study drug, so seven patients discontinued treatment (five kidney transplant patients and two liver transplant patients).
Patient demographics and baseline characteristics
Of the 92 patients enrolled, 73 were male and 19 were female. The mean ± SD age was 40.2 ± 11.5 years [Table 1]. Eighty-one patients (88.0%) underwent kidney transplantation and 11 patients (12.0%) underwent liver transplantation. The most common medical comorbidity at baseline was hypertension, experienced by 64 patients (69.6%).
The following concomitant medications were taken during the study: prednisolone (90 patients [97.8% however, two patients did not receive prednisolone, one patient had a history of hypertension and suffered a cerebrovascular event that may have been the reason for not receiving prednisolone; details of the other patient are not available]), pantoprazole (85 patients [92.4%]), mycophenolate (85 patients [92.4%]), nifedipine (36 patients [39.1%]), and amlodipine (42 patients [45.7%]). Overall, 21 patients (22.8%) received antibody induction therapy.
Exposure and adherence
The mean ± SD daily dose of prolonged-release tacrolimus for liver transplant patients at day 3 was 5.9 ± 2.4 mg, decreasing to 5.0 ± 2.2 mg at day 84. The mean ± SD daily dose of prolonged-release tacrolimus for kidney transplant patients at day 1 was 11.0 ± 2.7 mg, decreasing to 5.5 ± 1.5 mg at day 84. The mean ± SD fasting tacrolimus whole blood level for liver transplant patients at day 3 was 11.7 ± 2.5 ng/ml, decreasing to 8.4 ± 1.2 ng/ml at day 84. For kidney transplant patients, the mean ± SD fasting tacrolimus whole blood level at day 1 was 14.4 ± 4.4 ng/ml, decreasing to 9.0 ± 1.7 ng/ml at day 84. The mean ± SD duration of tacrolimus treatment exposure was 77.8 ± 22.7 days (median [range]: 86.0 [1.0–93.0*]; n = 87); (*one patient started tacrolimus 4 days before transplant [as per hospital practice]; their last visit was postponed by 3 days, hence, the total length of exposure was 93 days). Eight kidney transplant patients (9.9%) had their tacrolimus dose reduced. AEs that led to dose reduction were increased creatinine (n = 3), multiorgan dysfunction syndrome (n = 1), graft dysfunction (n = 1), graft dysfunction due to acute tubular necrosis (n = 1), acute cortical necrosis (n = 1), and fever (n = 1). There were 14 events of dose interruption (one patient experienced a rejection episode when the dose was interrupted). Of the AEs leading to treatment interruption, there were two episodes each of loose motions and high serum creatinine, and one episode each of suspected tubercular meningitis, acute kidney injury, high blood urea nitrogen, delayed graft function, ascites, bradycardia, loss of appetite, pain at stitch site, dysphagia, and hematuria. The overall treatment adherence was 99.2%.
A total of ten patients (11%) experienced the primary efficacy end-point of BCAR. Of the kidney transplant patients, 10 (12.3%) experienced BCAR ≥ Grade 1; seven patients were graded as Banff IA and three patients were graded as Banff 1B [Figure 1]. Of the liver transplant patients, none experienced BCAR according to the primary end-point of rejection activity index ≥4; one liver transplant patient experienced a rejection episode (rejection activity index 3) that did not reach the defined end-point. The median (range) time to first BCAR in kidney transplant patients was 6.5 (1.0–76.0) days. Of the ten rejection episodes that occurred in patients undergoing kidney transplantation, seven were corticosteroid sensitive, and three were corticosteroid resistant [Table 2]. Eight patients died, subsequently leading to graft loss.
|Figure 1: Biopsy findings among kidney and liver transplantation (n = 92) receiving prolonged-release tacrolimus. aPrimary end-point for kidney transplant patients: Biopsy-confirmed acute rejection Grade ≥1, according to Banff 2007 working classification of renal allograft pathology, within the first 12 weeks of transplant. Primary end-point for liver transplant patients: Biopsy-confirmed acute rejection with rejection activity index of ≥4, defined according to the 1997 Banff schema for grading liver allograft rejection, within the first 12 weeks of transplant|
Click here to view
Serum creatinine was observed at every visit to determine the renal function [Figure 2]a. For liver transplant patients, mean serum creatinine levels remained similar to baseline (0.79 ± 0.19 mg/dl): 0.99 ± 0.27 mg/dl at day 3, 0.84 ± 0.29 mg/dl at day 14, and 0.70 ± 0.05 mg/dl at day 84. For kidney transplant patients, mean serum creatinine levels decreased post transplantation as expected, then remained stable from day 3 to day 84 (serum creatinine was 6.16 ± 1.83 mg/dl at baseline, 1.40 ± 0.82 mg/dl at day 3, 1.15 ± 0.74 mg/dl at day 14, and 0.95 ± 0.30 mg/dl at day 84).
|Figure 2: (a) Serum creatinine and (b) lipid levels over time in liver and kidney transplant recipients. HDL: High-density lipoprotein, LDL: Low-density lipoprotein, SD: Standard deviation, TG: Triglycerides.|
Click here to view
Lipids, new-onset diabetes mellitus, and infections
A significant increase in all overall mean lipid parameters at day 28 (P< 0.05) and day 84 (P< 0.0001) compared with baseline levels was observed [Figure 2]b. Eleven of 70 patients (15.7%) had NODAT (excluding 22 patients with diabetes at baseline); nine were kidney transplant patients and two were liver transplant patients. There were seven incidences of infection reported in five patients. Four infections occurred in three kidney transplant patients, which were urinary tract infections (n = 2), sepsis (n = 1), source unknown and pneumonia (n = 1). Three infections occurred in two liver transplant patients, these were sepsis (n = 1), source unknown, bronchopneumonia (n = 1), and meningitis (n = 1).
A total of 11 patients (12.0%) reported treatment-emergent AEs [Table 3]. The incidence of AEs was similar across the transplant groups. Overall, the most common AE was an increase in blood creatinine that occurred in three patients (3.3%). Six patients all in the kidney transplantation group reported serious AEs of acute cortical necrosis, acute kidney injury, thrombotic microangiopathy, acute pancreatitis, cardiac arrhythmia, and lung consolidation.
|Table 3: Treatment-emergent adverse events, serious treatment-emergent adverse events, and treatment-emergent events leading to dose changes|
Click here to view
Laboratory investigations and vital signs
A small reduction from baseline to end of the study was observed in pulse rate, body weight, temperature, and blood pressure (both diastolic and systolic) among kidney transplantation patients (data not shown). In patients receiving a liver transplant, when comparing baseline to end of the study, pulse rate, body weight, and temperature remained the same whereas there was a marginal increase in blood pressure (data not shown). One kidney transplant patient had a clinically significant abnormal electrocardiogram at day 28 ± 1; this patient completed the study.
| Discussion|| |
The results for this first study of prolonged-release tacrolimus in de novo kidney and liver transplant recipients in India showed the immunosuppressive regimen was efficacious with a low incidence of acute rejection (10.9% overall) over a 12-week posttransplant period, with eight graft losses/deaths (8.7%) during the study. Acute rejection rates observed here in Indian patients are broadly in line with those reported in the literature for immunosuppression based on prolonged-release tacrolimus in other populations. For example, Albano et al. observed a rejection rate of 10.3% over 24 weeks, and studies have shown higher (20.4% over 24 weeks ) or lower (7.9% over 24 weeks ) rejection rates. Although reduction in tacrolimus levels may be a contributing factor for rejection episodes, in this study, of ten patients who experienced rejection episodes, only two patients had blood tacrolimus concentrations below the target levels of approximately 8-13 ng/ml.
Adherence to medication may be higher with once-daily prolonged-release tacrolimus compared with the twice-daily immediate-release formulation. In the current study, adherence with prolonged-release tacrolimus was high (99.2%) although the follow-up was not conducted over a sufficient period to accurately assess long-term adherence. Furthermore, it was beyond the scope of this study to assess cost-related adherence, which might be important in India.
There was a higher level of dose discontinuation and reduction in kidney transplant patients compared with liver transplant patients, which may reflect the ease at which the dose can be modified. Impaired renal function is one of the common AEs associated with immunosuppressive treatments in transplantation. In the current study, there was no evidence of nephrotoxicity, with renal function remaining stable in liver transplant patients. For kidney transplant patients, serum creatinine decreased posttransplant as the renal function of the patient improved, in line with expectations. Serum creatinine then remained steady from day 3 onward at a level comparable with other studies. This improvement/stability in renal function is consistent with the literature for immediate-release and prolonged-release tacrolimus.,
Immunosuppressive therapy may cause an imbalance in lipid and glucose metabolism., In this study, the incidence of NODAT (15.7%) was similar or lower than reports in the literature, where incidence can vary between 7% and 31% depending on the definition used.,,, In the current study, increases in lipid parameters over time were observed at day 28 and day 84 versus those at baseline, although all mean values remained within the normal range, apart from overall mean triglycerides at day 84 that showed slight elevation (158.2 ng/ml) above this level (normal <150 ng/ml). Some studies have shown that tacrolimus does not have a detrimental effect on lipid profile , whereas other studies have also shown modest increases in lipid concentration.
The risk of infection is increased with immunosuppressive agents such as tacrolimus. There was a low rate of infection in this study (5.4%) compared with reports in the literature, where infections have been reported in up to 24% in tacrolimus-treated transplant patients. Limitations of this study include the relatively short observation period of 12 weeks, smaller than anticipated sample size due to slow recruitment, especially for liver transplant patients, and the lack of a comparator arm. Nevertheless, due to the lack of publications on the efficacy and safety of tacrolimus in an Indian patient population, this study is an important addition to the evidence base for the use of prolonged-release tacrolimus in routine clinical practice in this patient population.
| Conclusion|| |
The results of this short-term study suggest that once-daily tacrolimus is well tolerated and efficacious, with a low incidence of acute rejection, in Indian patients undergoing kidney and liver transplantation.
We would like to acknowledge all additional investigators who participated in this trial.
Financial support and sponsorship
The study was sponsored by Astellas Pharma India Pvt. Ltd. Medical writing support in the development of this manuscript was provided by Michelle Utton-Mishra and Matthew Reynolds from SuccinctChoice Medical Communications and funded by Astellas Pharma Global Development, Inc.
Conflicts of interest
Bahadur MM received fees from Astellas for conducting clinical trial activities. ShahPis an employee of Astellas Pharma Inc.
| References|| |
Yabu JM, Vincenti F. Kidney transplantation: The ideal immunosuppression regimen. Adv Chronic Kidney Dis 2009;16:226-33.
Gheith O, Al-Otaibi T, Mansour H. Next-generation calcineurin inhibitors in development for the prevention of organ rejection. Transplant Res Risk Manage 2014;6:23-30.
Shipkova M, Armstrong VW, Oellerich M, Wieland E. Mycophenolate mofetil in organ transplantation: Focus on metabolism, safety and tolerability. Expert Opin Drug Metab Toxicol 2005;1:505-26.
Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev 2006:CD005161.
Webster A, Woodroffe RC, Taylor RS, Chapman Jr., Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005:CD003961.
van Boekel GA, Kerkhofs CH, Hilbrands LB. Treatment satisfaction in renal transplant patients taking tacrolimus once daily. Clin Ther 2013;35:1821-9.e1.
O'Regan JA, Canney M, Connaughton DM, O'Kelly P, Williams Y, Collier G, et al.
Tacrolimus trough-level variability predicts long-term allograft survival following kidney transplantation. J Nephrol 2016;29:269-76.
Posadas Salas MA, Srinivas TR. Update on the clinical utility of once-daily tacrolimus in the management of transplantation. Drug Des Devel Ther 2014;8:1183-94.
Silva HT Jr., Yang HC, Abouljoud M, Kuo PC, Wisemandle K, Bhattacharya P, et al.
One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo
kidney transplant recipients. Am J Transplant 2007;7:595-608.
Krämer BK, Charpentier B, Bäckman L, Silva HT Jr., Mondragon-Ramirez G, Cassuto-Viguier E, et al.
Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo
renal transplantation: A randomized phase III study. Am J Transplant 2010;10:2632-43.
Truneča P, Boillot O, Seehofer D, Pinna AD, Fischer L, Ericzon BG, et al.
Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant 2010;10:2313-23.
Albano L, Banas B, Klempnauer JL, Glyda M, Viklicky O, Kamar N, et al.
OSAKA trial: A randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. Transplantation 2013;96:897-903.
Tsuchiya T, Ishida H, Tanabe T, Shimizu T, Honda K, Omoto K, et al.
Comparison of pharmacokinetics and pathology for low-dose tacrolimus once-daily and twice-daily in living kidney transplantation: Prospective trial in once-daily versus twice-daily tacrolimus. Transplantation 2013;96:198-204.
Adam R, Karam V, Delvart V, Truneča P, Samuel D, Bechstein WO, et al.
Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the european liver transplant registry. Am J Transplant 2015;15:1267-82.
Caillard S, Moulin B, Buron F, Mariat C, Audard V, Grimbert P, et al.
Advagraf(®), a once-daily prolonged release tacrolimus formulation, in kidney transplantation: Literature review and guidelines from a panel of experts. Transpl Int 2016;29:860-9.
Varghese J, Reddy MS, Venugopal K, Perumalla R, Narasimhan G, Arikichenin O, et al.
Tacrolimus-related adverse effects in liver transplant recipients: Its association with trough concentrations. Indian J Gastroenterol 2014;33:219-25.
Sharma R, Rajasekar MR, Raghuvanshi A. Immunosuppression strategies after liver transplantation: A single centre experience in 57 liver transplant recipients. Indian J Surg 2007;69:187-90.
Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, et al.
Banff 07 classification of renal allograft pathology: Updates and future directions. Am J Transplant 2008;8:753-60.
Banff schema for grading liver allograft rejection: An international consensus document. Hepatology 1997;25:658-63.
Staatz C, Taylor P, Tett S. Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation. Nephrol Dial Transplant 2001;16:1905-9.
Kuypers DR, Peeters PC, Sennesael JJ, Kianda MN, Vrijens B, Kristanto P, et al.
Improved adherence to tacrolimus once-daily formulation in renal recipients: A randomized controlled trial using electronic monitoring. Transplantation 2013;95:333-40.
Kumarasamy N, Safren SA, Raminani SR, Pickard R, James R, Krishnan AK, et al.
Barriers and facilitators to antiretroviral medication adherence among patients with HIV in Chennai, India: A qualitative study. AIDS Patient Care STDs 2005;19:526-37.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9 Suppl 3:S1-155.
Budde K, Bunnapradist S, Grinyo JM, Ciechanowski K, Denny JE, Silva HT, et al.
Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo
kidney transplants: One-year results of phase III, double-blind, randomized trial. Am J Transplant 2014;14:2796-806.
Ciftci HS, Ayna TK, Caliskan YK, Turkmen A, Gurtekin M. Lipid parameters, doses and blood levels of calcineurin inhibitors in renal transplant patients. Indian J Clin Biochem 2013;28:164-8.
Lankarani KB, Eshraghian A, Nikeghbalian S, Janghorban P, Malek-Hosseini SA. New onset diabetes and impaired fasting glucose after liver transplant: Risk analysis and the impact of tacrolimus dose. Exp Clin Transplant 2014;12:46-51.
Deleuze S, Garrigue V, Delmas S, Chong G, Swarcz I, Cristol JP, et al.
New onset dyslipidemia after renal transplantation: Is there a difference between tacrolimus and cyclosporine? Transplant Proc 2006;38:2311-3.
Taylor DO, Barr ML, Radovancevic B, Renlund DG, Mentzer RM Jr., Smart FW, et al.
Arandomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: Decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant 1999;18:336-45.
Peraira JR, Segovia J, Arroyo R, Ortiz P, Fuertes B, Moñivas V, et al.
High incidence of severe infections in heart transplant recipients receiving tacrolimus. Transplant Proc 2003;35:1999-2000.
Takahashi K, Abe R, Usuki S, So M. Safety and efficacy of once-daily modified-release tacrolimus in kidney transplant recipients: Interim analysis of multicenter postmarketing surveillance in Japan. Transplant Proc 2014;46:406-10.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]