Prevention of organ rejection in renal and liver transplantation with extended release tacrolimus

Figures & data

Table 1 Studies in de novo kidney transplantation

Reference	Author	Year	Design (FU=follow-up)	Number of participants	Treatment	Outcome (AR=acute rejection, BPAR=biopsy proven acute rejection)
11	Albano	2013	Open label, parallel group randomized European adults being transplanted or re-transplanted, FU 24 weeks.	1251 (976 per protocol)	1-3 MMF + steroids 4 mycophenolate + basiliximab + periop steroids 1 TAC BID 0.2 2 TAC QD 0.2 3 TAC QD 0.3 mg/kg 4	TAC QD 0.2mg/kg was noninferior to TAC BID 0.2mg/mL (with steroids, MMF).
12	Tsuchiya	2013	Open label and prospective randomized controlled trial, FU 1 year.	102 (50 TAC QD)	Low dose TAC BID or QD. (6-10ng/mL induction, 4-6ng/mL maintenance	Protocol biopsy—overall 13.7% AR; no significant difference between groups. No significant difference in TAC tubulopathy or eGFR between groups. QD TAC dose was higher at most time points. The trough concentrations, peak levels and AUC were similar (AUC 280ng hour/mL at 14 days). There were no difference adverse events.
13	Krämer	2010	Multi-center 1:1-randomized parallel-group, noninferiority, double blind Phase III study, FU 24 weeks + open extension 12 months.	667	Pre-op 0.1mg/kg, post op 0.2mg/kg	PE – non inferiority; rates of BPAR at 24 weeks were 15.8% vs 20.4% for TAC BID vs QD (P=0.182). The 12 month patient survival was 97.5% vs 96.9%, and graft survival 92.8% vs 91.5%. Renal function and adverse events were similar in each group.
14	Cabello	2010	Randomized 1:1 comparative study, de novo renal transplant (expanded criteria donor, elderly recipients) FU 6 months.	27	TAC QID vs BID, 0.1mg/kg	There was no difference in trough levels from 24hrs to 6 months.There was good correlation between AUC and trough levels at 3 days. Renal function remained similar between groups. The BPAR was 0% and 16%, for TAC QD and BID, respectively.
15	Wlodarczyk	2009	Open label randomized comparative study, centers in Europe and Australia. FU 6 weeks.	122 randomized (66 PK profiles) 47 extension phase 1yr	TAC BID or QD	PE – The PK profile on day 1 showed an AUC for TAC QD as 30% lower but similar to TAC BID by day 14. The trough levels were similar by day 4. There was good correlation between AUC and trough levels. The efficacy and safety were similar between TAC QD and BID. In a 1yr extension (QD patients) – graft survival was 100% and 93.3% of patients were free from BPAR.
16	Silva	2007	Randomized, Phase III, open label, FU 12 months.	638	TAC BID, QD or cyclosporin.	PE – TAC BID/QD+MMF regimens were noninferior to Cyclosporine+MMF at 1 year based on a composite efficacy failure endpoint. The 1year patient and graft survival for TAC QD was 98.6%, and 96.7% respectively. Similar safety of TAC QD with BID.
19	Masutani	2014	Retrospective observational study de novo LRD renal transplant FU 12 months.	119 (29 TAC QD)	TAC QD vs BID	Doses required were higher in TAC QD treated patients (P<0.01) but trough levels and renal function remained similar. Protocol biopsy – subclinical rejection rates were similar between TAC QD and BID.The presence of IF and TA was less with TAC QD vs BID (42.2 vs 20.6%, P=0.04). Allograft rejection (borderline or above) was associated with IF/TA. No difference in tubular vacuolization or arteriolar hyaline change was seen between groups.
20	Jelassi	2011	Observational study with control group, FU 18 days.	12 (+ 18 controls)	TAC QD vs BID	The trough level and AUC were similar between groups, with a higher median dose used in TAC QD patients.
21	Andrés	2010	Retrospective single center observational study, with control group, FU 3.5-4 months.	49 (+30 controls)	TAC QD vs BID	Acute rejection rates were 10%, and 13% for TAC QD and BID, respectively. TAC QD patient survival was 98%, graft survival 96%, vs 100% survival and graft survival of 90% in TAC BID patients. The day 14 TAC QD level was 36% lower, and dose 21% higher in TAC QD patients.
22	Wlodarczyk	2012	Sub-study of randomized Phase III trial.	34	TAC QD vs TAC BID	Day 1 − there was a 16% decrease AUC with TAC QD. By day 3 exposure was similar. Trough levels were well correlated with AUC.
23	Kitada	2012	Retrospective observational study, FU 1 year.	50	TAC QD (oral) or BID (IV then oral)	In the TAC QD group, 3 month trough levels were lower, and at 12 months nonsignificantly lower. A significantly higher dose was required with TAC QD at 3 months and nearly identical at 12 months. Protocol and ad hoc biopsies showed AR in 4.3% and 11.1% for TAC QD and BID, respectively. Renal function was similar between groups.
24	Woillard	2011	Retrospective observational study, FU 12 months.	41 TAC QD 32TAC BID	TAC QD vs BID	Applied a model with TAC to measure TAC exposure with levels measured at 0, 1, 3 hours post-dose – this estimated AUC accurately (bias=0.1%) with good precision.
25	Crespo	2009	Retrospective observational study with historical controls, FU 6 months.	26	TAC QD vs BID	Efficacy and trough levels were similar with TAC QD or BID with increased dose in QD recipients.
26	Niioka	2012	Observational retrospective study, FU 28 days.	72	TAC QD vs BID	The trough level and AUC was 25% lower with TAC QD at day 28. Dose adjusted AUC in CYP3A*1 carriers was 25% lower than CYP3A*3/*3 for TAC QD. Reduced interpatient variability was seen with TAC QD. ABCB1 3435C>T polymorphism had no effect.
27	Ishida	2013	Retrospective observational study.	10 (+ 35 controls)	TAC QD vs BID	TAC QD – patient and graft survival were 100% at 15.7 months with no cases of BPAR using higher doses with TAC QD.
28	Niioka	2013	Retrospective observational.	97	TAC QD or BID	Genotype of CYP3A5 was significantly correlated with bioavailability (lowest with *1/*1). There was no effect of ABCBI alleles. The CYP3A5*1 and CYP3A5*3A3 significantly lower bioavailability in QD group compared to the BID group.
29	Takahashi	2014	Open label prospective noncomparative, nonintervention, observational study, FU 24 weeks.	256	TAC QD	Adverse event rates were as expected for TAC based therapy.
30	Fanous	2013	Retrospective, observational study, FU 12 months.	106 TAC QD 95 historical control TAC BID	TAC QD vs BID	There was similar renal function, NODAT, BK viremia, AR, and graft survival with TAC QD and BID. With TAC QD fewer dose adjustments were needed to reach steady state (P=0.03).
31	Hooff	2011	Open-label single-arm, follow up study of four Phase II studies − 2 de novo (kidney, liver), 2 stable conversion (kidney, heart) >90% Caucasian, FU 4 years.	240 (entry 6 weeks after de novo, 12 weeks after conversion)	TAC QD vs BID	Patient and graft survival were over 90% and freedom from BPAR was 90.0% with TAC QD.
32	Schenker	2009	Prospective observational study, FU 11 months, simultaneous pancreas-kidney transplantation.	14	TAC QD	Overall survival rates: patient—100%, kidney graft—100%, pancreas graft—93%. AR occurred in 38% of patients and 1 patient discontinued TAC QD due to psychotic symptoms.

Abbreviations: AR, acute rejection; AUC, area under the curve; BID, twice dail; BPAR, biopsy-proven acute rejection; FU, follow-up; QD, once daily; IF. interstitial fibrosis; TA, tubular atrophy; LRD, live related donor, MMF, mycophenolate mofetil; NODAT, new onset diabetes after transplantation; PE, primary endpoint; PK, pharmacokinetic; TAC, tacrolimus; eGFR, estimated glomerular filtration rate.

Table 2 Studies in de novo liver transplantation

Reference	Author	Year	Design	Number of participants	Treatment	Outcome
31	Hooff	2011	Open-label single-arm, follow up study of four Phase II studies – 2 de novo (kidney, liver), 2 stable conversion (kidney, heart) >90% Caucasian.	240 (entry 6 weeks after de novo, 12 weeks after conversion)	TAC QD vs BID	Patient and graft survival was over 90%. Freedom from BPAR was 92.6% for de novo liver transplantation.
34	Trunečka	2010	Multi-center 1:1-randomized, two-arm, parallel-group, double blind 24 weeks study + open extension 12 months.	475	TAC QD or BID	TAC QD was non-inferior; BPAR by 24wks occurred in 33.7% and 36.3% of patients for TAC BID and TAC QD (P=0.512), respectively. The BPAR requiring treatment rate at 12 months was 28.1 % and 24.7% for TAC BID vs QD respectively. Adverse events profiles were similar.
35	Fischer	2011	Randomized Phase II, multicenter, open label trial, FU 6 weeks.	129 (PK data for 77 patients)	TAC QD vs BID 0.10-0.15 mg/kg	In the first 24 hours the AUC was 50% less with TAC QD. At 14 days the AUC comparable but with higher QD doses. There was a strong correlation between AUC and trough levels. The efficacy at 6 weeks was similar.
36	Mita	2014	Prospective open label observational study, FU 1 week.	10	TAC IV to TAC QD conversion	TAC IV was converted to oral by a mean of 15.4 days. LFTs, glucose and renal function remained stable. The average conversion period duration was 4.6 days. There were no significant differences in AUC pre/post conversion using dose adjustment based on trough levels. The optimal initial dose conversion ratio from IV to oral was 1 to 8.
37	Urbina	2011	Retrospective analysis, FU 6 months.	50	TAC QD 1.5mg/kg or 0.75mg/kg	Overall adverse event rates: BPAR 10%, NODAT 22%, HTN 18%, 6% creatinine =>1.5mg/dL with 100% patient and graft survival.
38	Charco	2011	Prospective, observational, multicenter, longitudinal, 3-month study.	52	TAC QD	BPAR occurred in 13% of patients and graft survival was 100%. There was no change in mean glucose level and no cases hepatitis C relapse.
39	Uemoto	2014	Prospective, open label nonintervention, observational study, FU – de novo 1yr, conversion − 24 weeks	De novo 24 Conversion 122	TAC QD de novo or conversion from TAC BID	Infection related adverse events occurred in 25%, including CMV viremia in 12.5% of patients. Patient and graft survival at 1 year was 94.1% and 94.1%, respectively with AR occurring in 20.8% of patients.
40	Marubashi	2012	Nonrandomized cohort study with historical controls, FU 90 days.	16 (+14 historical controls)	TAC QD vs BID	More frequent dose adjustments were required with TAC QD. Higher total exposure occurred in in TAC QD treated patients. There was no change in renal dysfunction, AR, length of stay.
41	Sugawara	2011	Open label single center study, FU 20 weeks	12 (9 completed study)	iv TAC to TAC QD	There was similar AUC and safety profile with conversion (renal and liver function stable with no AR).

Abbreviations: AR, acute rejection; AUC, area under the curve; BID, twice daily; BPAR, biopsy-proven acute rejection; FU, follow-up; IV, intravenous; PK, pharmacokinetic; QD, once daily; TAC, tacrolimus; NODAT, new onset diabetes after transplantation; LFT, liver function tests; CMV, cytomegalovirus; HTN, hypertension.

Table 3 Studies of conversion to TAC QD in stable adult kidney transplant recipients

Reference	Author	Year	Design	Number of participants	Treatment	Outcome
18	Gaber	2013	Prospective conversion study using TAC-LCP, FU 21 days.	47	TAC BID to QD (LCP-Tacro tablets – Veloxis)	The mean conversion ratio was 1:0.71 resulting in consistent AUC and trough level after lower conversion dose. There were reduced fluctuations in levels after conversion (P<0.0001). 30% lower dose was required with TAC QD to maintain similar levels. Note—different preparation to Advagraf with increased bioavailability.
31	Hooff	2011	Open-label single-arm, follow up study of four Phase II studies − 2 de novo (kidney, liver), 2 stable conversion (kidney, heart) >90% Caucasian	240 (entry 12 weeks after conversion)	TAC BID to QD	Patient and graft survival was over 90%. Freedom from BPAR was 100% after conversion. Renal function remained stable.
42	Guirado	2011	Multicenter prospective observational study, FU 12 months.	1832	TAC BID to QD 1:1	Trough level decreased (mean at 12 months −9.1%) and the dose was increased by 1.24%. There was no change in eGFR, proteinuria, BP, lipids, LFTs, and glucose parameters. 8 patients developed AR (0.4%) and 34 discontinued TAC QD. 99.4% of patients preferred the once daily formulation.
43	Slatinska	2013	Retrospective observational crossover study, up to 12 month FU	589	TAC BID to QD 1:1	TAC dose remained similar with a nonsignificant decrease in trough levels (−12%). Renal function remained stable and there were 14 cases AR. Graft survival at 1 year was 96.3%. 28 patients discontinued TAC QD.
44	Kurnatowska	2011	Retrospective single center analysis, FU – 6 visits before/after (mean observation time after conversion 420 days)	52	TAC BID to QD	Conversion resulted in lower variation in blood levels and decreased trough levels. Renal function remained stable and there was a significant decrease in mean blood glucose levels. Fewer dose changes were required after conversion.
45	Sabbatini	2014	Cross-sectional and prospective open label nonrandomized conversion observational study, FU 6 months	310 (121 converted to TAC QD)	TAC BID to QD	At baseline nonadherence was 23.5% and associated with previous rejection episode (P<0.002), lower life satisfaction index, anxiety, low GFR (P<0.03) and reduced satisfaction with medical care/ medical staff. After conversion there was increased adherence (+36%, P<0.05 vs basal). Trough levels decreased (−9%) despite an increased dose (+6.5%).
46	Wu	2013	Retrospective cohort study of crossover, Chinese participants, FU 6 months.	199	TAC BID to QD 1:1,1.1,1.2	Trough TAC level decreased from 4.2 to 3.5 ng/mL (99 patients had a drop >20%). There was no change in renal function, lipids or glucose. 17% of patients discontinued TAC QD. Mean time from transplant to conversion was 8.3 years. When discontinuation occurred it was often initiated by patient concerns.
47	Ma	2013	Prospective open label study with Chinese participants, FU 12 weeks. + FU at 52 weeks (off protocol).	20 (two violated protocol)	TAC BID to QD 1:1	Trough levels decreased and dose was escalated after conversion with no episodes of acute rejection.
48	Sessa	2012	Observational longitudinal study of crossover to TAC QD	40	TAC BID to QD 1:1 conversion	Blood uric acid and homocysteine levels improved significantly after conversion. Numerical improvement in renal function (non-significant).
49	Hooff	2012	Open-label, multicenter replicate design study	69 (60 completed protocol)	TAC QD vs BID − 1:1 dose, 4 sequential 14 day cycles of alternating QD or BID.	Steady state level comparable for QD and BID. No change in renal function over the 8 week period. AUC and trough levels were well correlated.
50	Nakamura	2012	Observational conversion study, Japanese participants, FU 2 months	33	TAC BID to QD 1:1	Mean trough TAC level decreased after conversion (4.55 to 3.2ng/mL). There was no significant change in renal function, lipid or glucose levels and no AR or infection.
51	Lauzurica	2012	Multicenter, open, Phase lllb study, FU 12 weeks, mainly Caucasian	128 enrolled 91 evaluated for PE	TAC BID to QD 1:1	The change in creatinine clearance showed noninferiority, no BPAR, and no discontinuations. 59.1% required a dose change, and were mostly increases.
52	Uchida	2012	Prospective, observational, crossover, FU 4 weeks	26	TAC BID to QD 1:1	After conversion TAC trough levels decreased (4.9ng/mL to 4.24ng/mL) and renal function remained stable. Homeostasis model assessment of Beta-cell function, glycated hemoglobin levels and fasting insulin decreased significantly after conversion.
53	Midtvedt	2011	Prospective crossover study. FU 4-6 weeks Caucasian	20	TAC BID to QD 1:1	TAC trough levels decreased (6.6 to 5.4ng/mL) and peak levels decreased with no change in AUC. There was no change in insulin sensitivity or insulin secretion.
54	Kolonko	2011	Retrospective, crossover, stable renal TX (+SPK) FU 24 months	72	TAC BID to QD	eGFR increased at 12 (eGFR 57.1 to 60) and 24 months (eGFR 66).
55	Glowacki	2011	Prospective, single center, open-label study	17 (CYP3A5*1/*3 or 1/1) 15 (CYP3A5*3/*3)	TAC BID to QD 1:1	There was decreased dose-adjusted AUC in both groups. Trough levels were similar for non-expressors, and decreased in the expressor group (8.2 to 6.3ng/mL).
56	Iaria	2011	Observational conversion, FU 19 months	41	TAC BID to QD 1:1	Renal function remained stable. The TAC level decreased initially then normalized 6.9ng/mL baseline, 4.7ng/mL 3 months, 5.2ng/mL 6 months, 6.2ng/mL 12 months). There was no dose difference.
57	Jonge	2010	Retrospective single center study, conversion, FU 6 months or until Oct 1 2009	284	TAC BID to QD 1:1	The trough level decreased by 12.66% with a >20% decrease in 38.3% patients. The dose was increased in 52.5% patients and 28% patients required a dose increase of >20%. Dose changes were greater in the 1st year. Increased creatinine and lower hemoglobin was associated with increased dose requirement. Overall trough levels remained 9.09% lower.
58	Glick	2014	Prospective observational study 40% ethnic minority, FU 3-18 months	496	TAC BID to QD	Renal function remained stable, 7% of patients required dose decreases, 21% patients dose increases, and 16% of patients required a >30% dose increase. In South Asians 8% patients required a dose increase of >30%, East Asians 27.5% patients required increase doses >30% with similar baseline dose.
59	Ojea	2009	Observational study, FU 90 days	82 (38 90 day FU)	TAC BID to QD 1:1	7.6% of patients required dose adjustment. There was an initial reduction in TAC trough level at 7 days was then stable. Renal function and proteinuria levels remained stable.
60	Mecule	2010	Controlled crossover study, FU 6 months	40	TAC QD to BID 1:1	BP, renal function and cholesterol remained similar. Glycemia and triglyceride levels were reduced with TAC QD. 25% required TAC QD dose adjustment. There was no BPAR and TAC levels remained stable overall.
61	Tinti	2010	Observational crossover single center study, FU 6 months	31	TAC BID to QD	There was a small but significant decrease in TAC trough level after conversion. Renal function showed significant improvement after conversion (1.5 vs 1.6 mg/dl). There was no significant association between TAC trough level and renal function
62	Hougardy	2011	Retrospective observational crossover conversion study, FU 6 months	55	TAC BID to QD	The dose was significantly increased by 6 months. There was a decreased trough level at 180 days (8.05ng/mL to 6.3ng/mL). 35% patients required >30% dose increase. Renal function remained stable and there was no AR.
63	Wehland	2011	Crossover study, FU 1 year	41	TAC BID to QD	There was decreased trough and dose-normalized trough levels after conversion. Patients with the CYP3A5*3/*3 alleles required lower TAC doses of either BID or QD. There was a decline in trough TAC level after conversion in patients with *3/*3 alleles.
64	Calia	2011	Prospective observational crossover study, FU 6 months	78	TAC BID to QD	49 patients agreed to convert. There was no difference in baseline psychological variables. 8 patients switched back due to adverse events. Conversion resulted in increased patient initiated disclosure of having received a transplant (P<0.05). Patients who switched back showed less positivity and well-being (P<0.05)
65	Mecule	2011	Observational crossover study, FU 1yr	31	TAC BID to QD 1:1	TAC trough levels decreased (P=0.024) and in 19% of patients the dose was adjusted (50% patients increased dose). Similar rate of adjustment to pre-conversion and overall doses were similar.
66	Wu	2011	Prospective observational crossover study, open label, single center, FU 3 months	129	TAC BID to QD	There was a nonsignificant increased dose (4.7mg to 4.9mg). Trough TAC level decreased significantly after conversion. In 41/129 patients the decrease was >25% at day 7. There was reduced intra-patient trough variability.
67	Uchida	2014	Prospective conversion study, FU 24 weeks	26	TAC BID to QD 1:1	The trough level decreased at 4 weeks and was comparable at 24 weeks after dose increases. HOMA-beta assessment was significantly higher after conversion.
68	Alloway	2007	2 year follow up of conversion study, FU 2 years	67	Previously converted TAC BID to QD	2 year patient and graft survival was 100% and 98.5%, respectively. The BPAR incidence was 6%, multiple rejection rate 1.5%, and overall safety profile similar to the known TAC BID profile.
69	Bäckman	2014	Prospective observational multicenter conversion study, FU 90 days	224	TAC BID to QD 1:1	Trough level was significantly decreased at day 14 and at 12 weeks. Dose was increased in 22% and reduced in 15.6% patients. Trough level increased in 36.5% and decreased in 62.5%. There was no AR or graft loss. After conversion 19% of patients forgot medication less frequently and 55% reported no difference. 55% felt the change in dosing schedule was “better”.
70	Tsuchiya	2012	Crossover study, FU 120 days	43	TAC BID to QD 1:1	The trough level was comparable at 120 days. There was a significant increase insulin and HOMA-Beta score (P=0.091). Renal function, glucose, and HBAIc levels remained stable.
71	Hatakeyama	2012	Prospective observational cross-over study stable adult renal transplant Mean FU 14 months	12	TAC BID to QD 1:1	Trough level decreased from 4.8 to 3.6ng/mL within 1 month (P=0.0002). Renal function, potassium, glucose, HBAIc, and urine protein creatinine ration remained similar.
72	Rostaing	2012	Prospective multicenter conversion study, FU 24 weeks	301	Cyclosporine to TAC QD	Renal function was noninferior after conversion with no AR. Patient and physicians reported cosmetic improvement.
73	Veroux	2012	Crossover study with historical control group, FU 1 year	57	TAC BID to QD	After conversion there was improvement in gastrointestinal (GI) symptoms (P<0.001), GI health quality of life (P<0.05). At 12 months there was significantly lower abdominal pain, diarrhea, and reflux.
74	Boekel	2013	Prospective cohort study cross-over, FU 6 weeks	75	TAC BID to QD	Conversion resulted in increased satisfaction (P <0.001) and increased self-reported adherence (79.7% to 94.6%, P<0.001).
75	Wu	2014	Observational retrospective case control study	150	TAC BID vs TAC QD	CYP3A5 low expressor genotype had significantly higher trough TAC levels. In the high expressor group the coefficient of variation of trough levels was significantly reduced in the QD group.
76	Bunnapradist	2013	Phase III noninferiority trial of efficacy/safety conversion study, FU 12 months	326	TAC BID vs QD (tacrolimus-LCP)	There was no difference in the proportion with efficacy failure and safety was similar. There was increased discontinuation with TAC QD (12% vs 5%, P=0.028). The trough levels were similar. The dose in the QD group was lower than BID (P<0.0001) but starting dose higher. Note LCP formulation.
77	Alloway	2005	Open-label, multicenter study with crossover design, FU 21 days	70 (66 completed all PK profiles without error)	TAC BID to QD	Renal function remained stable with comparable safety profile and was well tolerated. AUC was highly correlated with trough levels. 30% of patients required dose adjustment. Nonsignificant reduction in AUC and trough levels. There was no difference in subsets based on gender, African-American or diabetes. With TAC QD there was less intra-subject variability.
78	Muduma	2014	Cost modeling based on effects of intra-patient variability in trough TAC levels		TAC BID to QD	Predicted 5 year saving £3415 in TAC QD group, driven mainly by lower dialysis costs.
79	Kuypers	2013	Randomized, multicenter, controlled trial, FU 9 months Randomized 2:1	219	TAC BID to QD	At 6 months 18.5% discontinued TAC QD. Electronic adherence monitoring showed that 88.2% and 78.8% of TAC QD and BID treated patients, respectively (P=0.0009) took the prescribed number of doses. In the BID group the percentage of missed doses was higher in the evening (11.7% morning, 14.2% evening (P=0.0035).

Note: Tacrolimus-LCP (veloxis Pharmaceuticals, Hørsholm, Denmark). Advagraf (Astellas Pharma inc., Tokyo, Japan).

Abbreviations: AR, acute rejection; AUC, area under the curve; BID, twice daily; BP, blood pressure; BPAR, biopsy-proven acute rejection; eGFR, estimated glomerular filtration rate; FU, follow-up; GFR, glomerular filtration rate; HBA1c, glycated liemoglobin (A1c); HOMA, liomeostasis model assessment; PE, primary endpoint; PK, pharmacokinetic; TAC, tacrolimus; QD, once daily; LFT, liver function tests; Tx, transplant; SPK, simultaneous kidney and pancreas.

Table 4 Studies of conversion to TAC QD in stable adult liver transplant recipients

Reference	Author	Year	Design	Number of participants	Treatment	Outcome
39	Uemoto	2014	Prospective, open label nonintervention, observational study, FU – de novo 1yr, conversion − 24 weeks.	Conversion 122	TAC QD de novo or conversion from TAC BID	Adherence of >90% increased from 84.1% to 96.5% post conversion. TAC trough level was 3.6ng/mL pre and 3.5ng/mL 1 week postconversion.
69	Bäckman	2014	Prospective observational multicenter conversion study, FU 90 days.	Liver 19	TAC BID to QD 1:1	Significantly decreased trough levels at day 4 to 14 and 12-week time points with no significant change in dose. Dose increased in 22% and reduced in 15.6% patients. Trough levels were increased in 36.5% and decreased in 62.5%. There were no episodes of AR or graft loss. 19% of patients forgot their medication less frequently and 55% reported no difference. 55% felt change in dosing schedule “better”
80	Weiler	2013	Prospective observational crossover single-center trial stable, FU 18 months.	61	TAC BID to TAC QD	With TAC QD 11 patients had dose escalations, and 10 dose reductions. Trough levels were significantly lower with TAC QD. There were no significant differences in clinical or biochemical parameters except for increased glycated hemoglobin with TAC QD.
81	Merli	2010	Crossover study adult, FU 6 months.	28	TAC BID to QD 1:1	In 43% of patients the dose was increased and in 24% the dose was reduced. TAC levels were stable by 45 days and there were no adverse events or changes in liver function.
82	Beckebaum	2011	Observational crossover study, FU 1 year.	125	TAC BID to QD 1:1	After 1 week trough levels decreased from 6.1 ng/mL to 5.5ng/mL (P=0.0016), and after 2 weeks to 5.5ng/mL (P=0.019). In 28.8% of patients TAC level was >25% lower, 24% TAC >25% higher. TAC doses were increased by week 2, month 1 and month 3. TAC dose decreased at month 6 and 9 in 1/3 patients. LFTs, renal function and HBAIc remained stable, with no AR over 12 months. Nonadherence decreased from 62.4% to 36% (P<0.0001). Baseline adherence was significantly higher in patients converted >2 years after and if <60 years old.
83	Zhang	2011	Chinese open label multicenter study, one way conversion, FU 84.	83	TAC BID to QD 1:1	Day 1 AUC remained stable and at day 84 was reduced by 17%, deemed outside the bioequivalent range. Doses increase by 14% and there was good correlation between AUC and trough levels.
84	Dopazo	2012	Observational multicenter study, FU 6 months.	187	TAC BID to QD 1:1	There was significantly decreased trough levels at 1 month from 5.4ng/mL to 4.4ng/mL (P=0.013) and normalized by 6 months. LFTS remained stable overall and AR occurred in 2/187 patients.
85	Dumortier	2013	Retrospective, observational, single center conversion study, FU 24 months .	394	TAC BID to QD 1:1	Trough level decreased after conversion (P<0.05). 9% patients discontinued TAC QD. LFTs, renal function, diabetes, dyslipidemia remained unchanged. 7 patients developed BPAR in the TAC QD group.
86	Giannelli	2013	Observational crossover study, FU 12-24 months.	65	TAC BID to QD 1:1	Dose stabilized in 90% of patients by 3 months after conversion. LFTS, glucose, lipids, and BP remained stable after conversion. There was significant improvement of renal function (MDRD GFR 71 to 82, P 0.001).
87	Comuzzi	2010	Observational conversion study, FU 14 days.	36	TAC BID to QD 1:1	There was no significant change in trough level or dose between times 0, 7 days, 14 days. LFTs and renal function remained stable with no AR.
88	Florman	2005	Open label, multicenter, single sequence 4 period crossover design, FU 56 days (91.9% Caucasian)	72 (62 all 4 PK profiles)	Crossover TAC BID and QD. 1:1	AUC decreased by 11.21% after conversion (not significant). 80% did not require dose adjustment. Intra-subject variability was less with TAC QD. There was a strong correlation between AUC and trough levels. Tolerability was similar and only 1 patient developed BPAR after conversion. There were no new cases of diabetes.
89	Eberlin	2013	Crossover study, FU 12 months	65	TAC BID to QD	Pill bottle opening was monitored electronically. Dosing compliance increased after conversion (P=0.008). Timing compliance significantly increased after conversion (P=0.003). The missed dose rate was twice as high in the TAC BID group. There was no difference in compliance changes between subgroups of patients converted at different times posttransplantation.
90	Valente	2013	Observational, retrospective crossover study, Stable adult, peripheral center, median FU 21 months.	34	TAC BID to QD 1:1	Adherence visual analogue rating increased from 86 to 90% and BAASIS score reduced from 45% to 35%. Renal function improved − 6mL/min increased clearance.
91	Florman	2007	2 year post conversions data for Florman 2005. Multi-center observational study.	56	TAC QD	Mean dose remained fairly constant (range 5.5-6mg). Most patients did not require dose changes. BPAR incidence at 2 years was 5.8%. The incidence of infections and metabolic complications as expected for TAC.
92	Sańko-Resmer	2012	Multicenter, open-label, Phase III study, FU 12 weeks	98	TAC BID to QD 1:1	Renal function remained stable. 74.5% required no dose adjustment and trough levels decreased from 7.5ng/mL to 6.5ng/mL (P=<0.0001). There were no episodes of AR. There was decreased inter and intra-patient variability.
93	Alloway	2014	Prospective open label, multicenter conversion study, FU 21 days + extension study to 52 weeks)	57 (core study) 43 extension phase	TAC BID to QD (LCP-Tacro)	The mean conversion ratio was 0.71. The AUC was similar. Max concentration and fluctuations significant reduced. One patient discontinued QD (unrelated to the drug) during the core study and 3 discontinued during the extension phase. 1 episode of AR occurred during the extension phase. Note the LCP formulation of TAC was used in this study.
94	MarinGomez	2009	Observational crossover study, FU 193 days	79	TAC BID to QD 1:1	Trough concentration decreased at 1 month but was comparable by 6 months. The majority of patients did not require dose adjustment – the dose increased in 11.4%, 14.3% and 10% of patients at 1, 3, 6 months respectively. Renal function and liver function remained stable.

Note: Tacrolimus-LCP (veloxis Pharmaceuticals, Horsholm, Denmark).

Abbreviations: AR, acute rejection; AUC, area under the curve; BID, twice daily; BPAR, biopsy-proven acute rejection; FU, follow-up; LFTs, liverfunction tests; PK, pharmacokinetic; QD, once daily; TAC, tacrolimus; BP, blood pressure; HBA1c, glycated hemoglobin (AIe); eGFR, estimated glomerular filtration rate; BAASIS, Basel Assessment of Adherence to medication scale.