Transplant International ISSN 0934-0874
`
`O R I G I N A L A R T I C L E
`
`Efficacy, safety, and immunosuppressant adherence in
`stable liver transplant patients converted from a
`twice-daily tacrolimus-based regimen to once-daily
`tacrolimus extended-release formulation
`Susanne Beckebaum,1,2 Speranta Iacob,1,3 Dani Sweid,2 Georgios C. Sotiropoulos,2 Fuat Saner,2
`Gernot Kaiser,2 Arnold Radtke,2 Christian G. Klein,1,2 Yesim Erim,4 Sabina de Geest,5 Andreas Paul,2
`Guido Gerken1 and Vito R. Cicinnati1,2
`
`1 Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
`2 Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
`3 Gastroenterology and Hepatology Center, Fundeni Clinical Institute, Bucharest, Romania
`4 Department of Psychosomatic Medicine and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
`5 Institute of Nursing Science, University of Basel, Basel, Switzerland
`
`Keywords
`adherence, efficacy, extended-release
`tacrolimus, immunosuppression, safety.
`
`Correspondence
`Susanne Beckebaum MD, Interdisciplinary
`Liver Transplant Unit, University Hospital
`Essen, OPZ 2, Ebene A1, Hufelandstr. 55,
`45122 Essen, Germany. Tel.: +49 201 723
`1102; fax: +49 201 723 1113; e-mail:
`susanne.beckebaum@uni-due.de
`
`Conflicts of Interest
`None.
`
`Received: 2 December 2010
`Revision requested: 1 January 2011
`Accepted: 9 March 2011
`Published online: 5 April 2011
`
`doi:10.1111/j.1432-2277.2011.01254.x
`
`Summary
`
`The aim of this study was to determine the efficacy, safety, and immunosup-
`pressant adherence in 125 stable liver transplant (LT) patients converted from
`twice-daily tacrolimus (TAC BID) to once-daily TAC (TAC OD). Tacrolimus
`trough levels,
`laboratory parameters, metabolic disorders,
`selected patient
`reported outcomes, and adverse events were assessed. Mean TAC trough level
`concentration was 6.1 ± 2.3 ng/ml at study entry, decreased to 5.5 ± 2.1 ng/ml
`(P = 0.016) and 5.5 ± 2.2 ng/ml (P = 0.019) after 1 and 2 weeks, respectively,
`and tended to equal the baseline value during further follow-up. At week 1,
`TAC concentrations were lower in 62.4% of patients and higher in 36.0% when
`compared with baseline. Renal and cardiovascular risk factors remained stable
`and no rejection episodes occurred over 12 months. Adverse events were con-
`sistent with the safety profile known from previous studies with TAC BID.
`Nonadherence measured by the ‘‘Basel Assessment of Adherence Scale to
`Immunosuppressives’’ was evident in 66.4% at study entry and decreased to
`30.9% postconversion (P < 0.0001). Prevalence of nonadherence at baseline
`was significantly higher in patients converted >2 years after LT and in those
`£60 years of age. Conversion to TAC OD is safe, enhances immunosuppressant
`adherence and should be accompanied by a close TAC level monitoring during
`the initial period.
`
`Introduction
`
`immunosuppressive
`Life-long intake and complexity of
`medication make patients prone to nonadherent behavior
`which contributes to rejection and graft loss [1]. Drug
`adherence declines over the course of time in patients
`after organ transplantation and depends on the type of
`medication, the number of drugs to be taken and the
`number of daily doses [2]. A study in kidney transplant
`
`(OD) dosing
`patients demonstrated that once-daily
`resulted in improved adherence when compared with
`twice-daily (BID) dosing [3]. Similarly, a review of 76
`studies using electronic monitoring device to assess medi-
`cation adherence showed that the prescribed number of
`doses per day was inversely related to adherence [4].
`The
`introduction of OD tacrolimus
`(TAC OD)
`extended-release
`(XL)
`formulation,
`administered in
`the morning, may be associated with better treatment
`
`666
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`ª 2011 The Authors
`Transplant International ª 2011 European Society for Organ Transplantation 24 (2011) 666–675
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`Ex. 1055-0001
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`

`
`Beckebaum et al.
`
`Conversion of LT patients to once-daily tacrolimus formulation
`
`life. A previously published
`adherence and quality of
`phase 3 randomized study in de novo liver transplant
`(LT) patients compared TAC OD with TAC BID, both
`combined with corticosteroids [5]. One year results dem-
`onstrated that the new TAC formulation-based regimen
`had a similar efficacy and safety profile when compared
`with TAC BID. A pharmacokinetic conversion study in
`stable LT recipients reported equivalent, but on average
`11% lower AUC0–24 after a milligram (mg)-for-mg dose
`conversion [6]. In a de novo study of LT patients, sys-
`temic exposure (AUC0–24) on day 1 was approximately
`42% lower for TAC OD than for TAC BID at equivalent
`doses, whereas values at steady state (day 14 and week 6)
`were similar for both formulations [7]. To our knowl-
`edge, no prospective studies have been published in full
`addressing selected patient reported outcomes (PROs)
`(e.g., adherence to immunosuppressive medication or
`patients’ treatment preferences) in stable LT patients who
`have been switched from a conventional TAC-based regi-
`men to the new TAC formulation. We
`therefore
`addressed this issue over a 1-year study period. Moreover,
`we assessed metabolic and cardiovascular risk factors and
`potential adverse events postconversion.
`
`Patients and methods
`
`Design and sample
`This study was designed as a prospective, single center,
`observational, noninterventional study with 8 time points:
`preconversion (baseline), weeks 1 and 2, and months 1, 3,
`6, 9, and 12 after conversion (Fig. 1).
`
`Adult LT patients were eligible for the study if they (i)
`had received a primary deceased or living related LT
`>6 months prior to study entry and (ii) were willing to
`comply with the study protocol. Exclusion criteria were
`(i) the presence of systemic infection requiring therapy,
`(ii) pregnant and nursing women, (iii) signs of decom-
`pensated liver disease, (iv) severe or recurrent gastrointes-
`tinal complaints, or (v) an episode of chronic or acute
`graft rejection within 12 months of study entry.
`As this was an observational study, the assignment of
`patients to the new TAC formulation fell within current
`practice in accordance with the terms of the marketing
`authorization and the prescription of the medicine was
`clearly separate from the decision to include a given
`patient in the study. No diagnostic or monitoring proce-
`dures other than those required in the course of current
`clinical practice were applied to the patients. The study
`was approved by the Institutional Review Board of the
`University of Duisburg-Essen (IRB 07-3557). All patients
`gave written informed consent in accordance with the
`Declaration of Helsinki 2000 and the Declaration of
`Istanbul 2008.
`
`Therapeutic protocol and adjunct immunosuppressants
`The switch from a TAC BID (PrografÒ; Astellas Phrama
`US, Inc., Deerfileld, IL, USA) to a TAC OD (AdvagrafÒ;
`Astellas Phrama US, Inc., Deerfileld, IL, USA) regimen
`was based on a 1:1 mg proportion. We instructed our
`patients to administer TAC BID or the new TAC XL
`
`Twice-daily tacrolimus
`(TAC BID)-based regimen
`
`n = 137
`
`Screened
`
`n = 125
`
`n = 12
`
`Once-daily tacrolimus (TAC QD) extended-release formulation
`n = 1 loss of
`follow-up
`
`n = 119
`Follow-up completed
`
`n = 5 death
`
`n = 110 maintained
`on TAC QD
`n = 9 reconversion
`to TAC BID during
`observation period
`
`Time (months)
`
`Screening
`
`Base-
`line
`Week 1 Month 1
`
`Week 2
`
`Month 3
`
`Month 6
`
`Month 9
`
`Month 12
`
`Study visits
`
`Figure 1 Study design and flow chart with disposition of patients. A total of 137 patients were screened; 125 patients successfully completed
`the screening phase and 12 were withdrawn for reasons of severe decompensated liver disease [fibrosing cholestatic hepatitis C (n = 1), recurrent
`alcohol-related graft failure (n = 1), severe diarrhea (n = 3), chronic rejection (n = 3), acute cellular rejection (n = 1), inability (n = 1) and unwill-
`ingness to comply to the study protocol (n = 1)]. During the study, one patient was lost to follow-up after 21 days and five patients died because
`of sepsis (n = 3), recurrent neuroendocrine tumor (n = 1) and fibrosing cholestatic hepatitis C (n = 1) after 233, 327, 328, 23, and 79 days,
`respectively. A total of 119 patients completed 12 months of follow-up; of those, n = 110 had continuous administration of TAC OD formulation
`throughout the study; whereas nine patients were switched back to TAC BID because of adverse events.
`
`ª 2011 The Authors
`Transplant International ª 2011 European Society for Organ Transplantation 24 (2011) 666–675
`
`667
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`

`
`Conversion of LT patients to once-daily tacrolimus formulation
`
`Beckebaum et al.
`
`formulation according to the product information pro-
`vided by the company.
`At baseline and during follow-up, TAC doses were
`adjusted to maintain target trough levels of 4–8 ng/ml.
`TAC levels were measured in our central
`laboratory at
`baseline, weeks 1 and 2, months 1, 3, 6, 9, and 12 using
`the affinity column-mediated immunoassay (Dimension
`RxL Max; Dade Behring, Eschborn, Germany).
`A total of 55 patients were receiving adjunctive immu-
`nosuppressive medications prior to study entry. Sirolimus
`(SRL) was adjusted to maintain target trough levels of
`5–7 ng/ml. Concomitant prednisone dose was low, rang-
`ing from 2.5 mg to 7.5 mg/day.
`
`Primary and secondary objectives
`
`The primary objective of the study was to determine the
`event
`rate of biopsy-proven acute
`rejection within
`12 months postconversion. Secondary objectives included
`patient and allograft survival, renal function [measured by
`serum creatinine and calculated glomerular filtration rate
`(cGFR)], liver enzymes, adverse events and PROs (adher-
`ence to immunosuppressive regimen and patients’ prefer-
`ence with TAC OD versus TAC BID) at 1 year.
`
`Clinical and biochemical parameters
`
`Patient and graft survival and the time to and the event
`rate of biopsy-proven acute rejection episodes were
`assessed throughout the study. A liver biopsy was per-
`formed if clinical signs and/or laboratory parameters were
`suspicious of the occurrence of a rejection episode. Histo-
`logical evaluation of the biopsy was performed according
`to the Banff criteria [8]. Graft loss was defined as retrans-
`plantation or death.
`Blood pressure was recorded at each visit. Arterial
`hypertension was diagnosed when systolic blood pressure
`was ‡140 mmHg or diastolic blood pressure ‡90 mmHg
`and/or in case of current antihypertensive treatment [9].
`Diabetes was defined according to the American Diabetes
`Association Diagnostic Criteria [10]. Hypercholesterol-
`emia was diagnosed in patients with fasting total
`cholesterol
`level of >200 mg/dl or the need for choles-
`terol-lowering agents; hypertriglyceridemia was defined as
`fasting total triglyceride level of >200 mg/dl or the need
`for triglyceride-lowering agents.
`Safety was determined at each visit based on physical
`examination, vital sign measurements, adverse events, and
`results of laboratory tests. Patients had regular monitoring
`of laboratory values at months 0, 1, 6, 9, and 12. HbA1c
`was determined at months 0, 1, 6, and 12; cGFR was cal-
`culated based on the abbreviated modification of diet in
`renal disease (MDRD) equation [11].
`
`Patient reported outcomes
`
`Self-reported adherence with immunosuppressive therapy
`was assessed at baseline and at month 12 using the ‘‘Basel
`Assessment of Adherence Scale to Immunosuppressives’’
`(BAASIS). This instrument consists of a four-item vali-
`dated questionnaire and a Visual Analog Scale (VAS)
`[12,13]. The BAASIS is administered as a patient inter-
`view, and the recall period comprises the last 4 weeks.
`The second part of the BAASIS is a 100-point VAS
`scale. Patients score their medication adherence during
`the past 4 weeks from 0 (immunosuppressive medication
`never taken as prescribed) to 100 (immunosuppressive
`medication always taken as prescribed) [14]. Medication
`adherence is assessed as a continuous variable by the VAS
`with no defined cut-off for nonadherence.
`Patients’ preference with the treatment regimen was
`also assessed by a self-report at the end of the observa-
`tion period. More
`specifically, patients were
`asked
`whether they preferred to remain on TAC OD or return
`to TAC BID regimen. Patients who decided to remain
`on TAC OD formulation after study completion were
`asked at month 12 to specify the reason for drug contin-
`uation.
`We further investigated the possible implications of
`therapeutic complexity, reflected by the number of pre-
`scribed drugs and the dosing frequency, on drug adher-
`ence. For this purpose, we reviewed the patients’ records
`and listed all of the concomitant medication for those
`patients (n = 110) in whom adherence was measurable at
`baseline and follow-up, and who were maintained on
`TAC OD throughout
`the study. We also investigated
`whether there was a correlation between age and adher-
`ence and a difference in the adherence of patients con-
`verted during a shorter (£2 years) versus a longer time
`period (>2 years) after LT.
`
`Statistical analysis
`
`Continuous data were expressed as mean ± SD (unless
`otherwise indicated). Friedman test was used to compare
`continuous values at distinct time points for global com-
`parison. An overall a = 0.05 was chosen to indicate statis-
`tical
`significance. A Wilcoxon Signed Rank test was
`carried out to compare continuous values at two distinct
`time points (visits) and to compare the follow-up data
`with the baseline data. Categorical data were described as
`frequencies of the subjects with a specific characteristic.
`Chi-square test was used to compare categorical data and
`the McNemar test was used to compare paired categorical
`variables. The Pearson’s rank correlation coefficient was
`used to measure the degree of association between two
`quantitative variables. Two-tailed P values <0.05 were
`
`668
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`ª 2011 The Authors
`Transplant International ª 2011 European Society for Organ Transplantation 24 (2011) 666–675
`
`Ex. 1055-0003
`
`

`
`Beckebaum et al.
`
`Conversion of LT patients to once-daily tacrolimus formulation
`
`considered statistically significant. Statistical analyses were
`performed using SPSS software 15.0 (SPSS Inc., Chicago,
`IL, USA).
`
`postconversion. No
`12 months
`at
`bilirubin
`and
`rejection episodes occurred during the course of
`the
`study.
`
`Results
`
`Patient and graft survival
`
`Sample characteristics
`Between September 2008 and June 2009, 137 LT recipi-
`ents with TAC BID-based immunosuppression were
`screened for eligibility criteria (Fig. 1). Of these, 125 LT
`recipients were switched to TAC OD, whereas 12 patients
`did not qualify for the study. During the study period,
`one patient was lost to follow-up and five patients died.
`A total of 119 patients completed 12 months of follow-up.
`Of
`those, 110 patients were maintained on TAC OD
`throughout the study; whereas nine were withdrawn from
`the TAC XL formulation and reconverted to TAC BID
`because of adverse events. Table 1 shows baseline charac-
`teristics of the study population. Patients had a median
`age of 53 years (range: 19–74 years). The time period
`between LT and enrollment in the study group ranged
`between 6.1 and 251 months.
`
`TAC trough levels and dose requirements
`
`At study entry, the mean TAC trough level concentration
`was 6.1 ± 2.3 ng/ml (Table 2), followed by a significant
`decline to 5.5 ± 2.1 ng/ml (P = 0.016) and 5.5 ± 2.2 ng/
`ml (P = 0.019) after 1 and 2 weeks, respectively. At week
`1, TAC concentrations were lower in 62.4% of patients
`and higher in 36.0% of patients, compared with baseline.
`In 28.8% and 24.0% of patients, TAC concentrations were
`>25% lower and >25% higher
`than preconversion,
`respectively.
`Compared with the start of the study, TAC doses were
`significantly higher at week 2 (P = 0.003), month 1
`(P = 0.003), and month 3 (P = 0.01), respectively resulting
`in a significant TAC level increase at month 1 when com-
`pared with week 2 (P = 0.014) and stable TAC levels during
`further follow-up. The highest proportion (nearly one-
`third) of patients with TAC dose increases was observed at
`week 2; in 15 patients (12.1%), the TAC dose was increased
`>25% (>25–50% in 10 patients, >50–75% in none, >75–
`100% in three patients and >100% in two patients).
`At months 6 and 9, the dose was decreased in nearly
`one-third of patients. Consequently,
`the mean TAC
`concentration at month 12 tended to be lower than TAC
`levels on previous visits (Table 2).
`
`Graft function and graft rejection at month 12
`
`There were no significant changes in alanine amino-
`transferase
`(ALT),
`aspartate
`aminotransferase
`(AST),
`
`The Kaplan–Meier 12-month-estimated patient and allo-
`graft survival rates were both 96%. Three patients died
`during follow-up because of sepsis 233, 327, and 328 days
`postconversion and one patient died because of a recur-
`rent neuroendocrine tumor after 23 days. One patient
`with fibrosing cholestatic hepatitis C experienced graft
`failure during the study, was relisted, and died on the
`waiting list 79 days after study entry.
`
`Table 1. Patients’ baseline characteristics.
`
`Variable
`
`Patients (n = 125)
`
`Age (years)
`Male gender (%)
`Primary indication for LT (%)
`HCV
`ALD
`AIH, PBC, PSC
`HCC
`HBV/HBV + HDV
`Cryptogenic
`Acute liver failure
`Wilson’s disease
`Others
`Time LT-enrollment (months)
`<1 year, 1–5 years, 6–10
`years, >11 years after LT (%)
`Arterial hypertension (%)
`Antihypertensive medication (%)
`No. antihypertensive drugs:
`n = 1, 2–3, 4–5 (%)
`Hypercholesterolemia/
`hypertriglyceridemia (%)
`Lipid lowering agents (statins and/or
`fibrates) (%)
`Diabetes (%)
`Oral medication and/or insulin
`TAC-based immunosuppression (%)
`Plus mycophenolate mofetil
`Plus steroids
`Plus sirolimus
`TAC monotherapy/TAC-based
`double/triple immunosuppression (%)
`
`51 ± 13.9
`79 (63.2)
`
`23 (18.4)
`19 (15.2)
`16 (12.8)
`12 (9.6)
`11 (8.8)
`11 (8.8)
`12 (9.6)
`5 (4.0)
`16 (12.8)
`77.4 ± 59.6
`2 (1.6), 62 (49.6),
`37 (29.6), 24 (19.2)
`75 (60.0)
`68 (54.4)
`28 (22.4), 38 (30.4),
`2 (1.6)
`33 (26.4)/26 (20.8)
`
`9 (7.2)
`
`39 (31.2)
`27 (21.6)
`
`39 (31.2)
`25 (20.0)
`8 (6.4)
`70 (56.0)/36 (28.8)/
`19 (15.2)
`
`Values are expressed as mean ± SD or percentages.
`LT, liver transplantation; HCV, hepatitis C virus; ALD, alcoholic liver
`disease; AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis;
`PSC, primary sclerosing cholangitis; HCC, hepatocellular carcinoma;
`HBV, hepatitis B virus; HDV, hepatitis D virus; BMI, body mass index;
`TAC, tacrolimus.
`
`ª 2011 The Authors
`Transplant International ª 2011 European Society for Organ Transplantation 24 (2011) 666–675
`
`669
`
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`
`

`
`Conversion of LT patients to once-daily tacrolimus formulation
`
`Beckebaum et al.
`
`Renal function and cardiovascular risk factors
`
`The evolution of renal function is shown in Table 3. The
`results indicate that serum creatinine values, urea, and
`cGFR remained stable throughout the 12 months post-
`conversion.
`A total of 46 patients (36.8%) had no concomitant
`antihypertensive,
`antidiabetic
`and/or
`lipid
`lowering
`agents. Antihypertensive medication was administered in
`54.4% and 62.5% of patients at baseline (Table 1) and at
`month 12, respectively. The mean number of antihyper-
`tensive drugs per patient diagnosed with arterial hyper-
`tension remained similar (1.67 ± 0.96 at baseline vs.
`1.74 ± 1.00 after 12 months, P = 0.634) throughout the
`study. The doses of antihypertensive medication were
`decreased in three patients during follow-up. Three
`patients were diagnosed with borderline hypertension [9]
`at baseline and developed manifest arterial hypertension
`at month 12.
`Fasting glucose levels (Table 3) and HbA1c values
`(6.27 ± 3.36%, 5.85 ± 1.04%, 6.32 ± 1.96%, and 6.07 ±
`0.92% at baseline, months 1, 6, and 12, respectively)
`remained stable during 12 months of
`follow-up. Three
`and two patients were prescribed sulfonylureas (glimepi-
`ride) or glinides (repaglinide, nateglinide) at baseline and
`at month 12; two patients and one patient were treated
`with alpha-glucosidase
`inhibitors at baseline and at
`month 12, respectively. Insulin-dependent diabetes was
`apparent in 22 patients at baseline, compared with 24
`patients at month 12 (P = 0.248). There was one case
`with de novo diabetes mellitus at month 12.
`There was no significant difference in body mass index
`(BMI) before TAC conversion and at month 12 postcon-
`version (mean BMI 26.3 ± 5.1 kg/m2 vs. 26.4 ± 5.0 kg/
`m2, P = 0.534). At study entry, hypercholesterolemia was
`apparent in 26.4% of patients, hypertriglyceridemia in
`20.8% of patients and combined hyperlipidemia in 12.8%
`of patients. A statin was withdrawn in one patient and
`was newly prescribed in another patient during follow-up.
`Lipid values did not
`change
`significantly (Table 3)
`throughout the study.
`
`Adverse events
`
`The postconversion safety profile of TAC OD was unre-
`markable and was consistent with the known adverse
`events for patients treated with TAC BID. During the
`study period, most TAC OD-related adverse
`events
`(Table 4) reported were mild or moderate and short-
`lived. One patient experienced tumor recurrence, but no
`de
`novo malignancies were
`reported
`during
`the
`12 months. Nine patients were reconverted to TAC BID
`because of side effects: Five patients were withdrawn
`
`****P=0.011forglobalcomparisonofTAClevelsatdistincttimepointsaccordingtoFriedmantest.
`***P=0.001forglobalcomparisonofdosesatdistincttimepointsaccordingtoFriedmantest.
`*P<0.005vs.baseline;**P<0.05vs.baseline.
`
`0.246
`
`0.634
`
`0.205
`
`0.130
`
`0.014
`
`0.727
`
`0.016
`
`–
`
`5.6±2.1
`65(59.1)
`6(5.5)
`25(22.7)
`6(5.5)
`20(18.2)
`0.622
`4.2±2.9
`
`n=110
`Month12,
`
`6.1±2.6
`66(58.9)
`11(9.8)
`33(29.5)
`6(5.4)
`13(11.6)
`0.019
`4.3±2.9
`
`n=112
`Month9,
`
`5.9±2.6
`58(50.9)
`4(3.5)
`33(28.9)
`9(7.9)
`23(20.2)
`0.138
`4.4±3.0
`
`n=114
`Month6,
`
`5.7±2.1
`68(59.1)
`6(5.2)
`21(18.3)
`12(10.4)
`26(22.6)
`0.962
`4.5±3.0**
`
`n=115
`Month3,
`
`5.9±2.2
`66(55.4)
`9(7.6)
`22(18.5)
`11(9.2)
`31(26.1)
`0.169
`4.5±2.9*
`
`n=119
`Month1,
`
`5.5±2.2**
`68(54.8)
`4(3.2)
`18(14.5)
`15(12.1)
`38(30.6)
`0.004
`4.4±2.8*
`
`n=124
`Week2,
`
`5.5±2.1**
`80(64.0)
`8(6.4)
`12(9.6)
`11(8.8)
`33(26.4)
`0.144
`4.2±2.7
`
`n=125
`Week1,
`
`6.1±2.3
`
`–
`
`–
`
`–
`
`–
`
`–
`
`–
`
`4.1±2.7
`
`n=125
`Baseline,
`
`P-valueversuspreviousvisit
`(ng/ml,mean±SD)
`Predoseconcentrations****
`Nochange(%)
`TACdosedecrease>25%(%)
`Dosedecreased(%)
`TACdoseincrease>25%(%)
`Doseincreased(%)
`P-valueversuspreviousvisit
`Dose***(mg,mean±SD)
`
`Table2.Once-dailytacrolimus(TACOD)doses,doseadjustmentsfrompreviousvisitovertimeandTACODpredoseconcentrations.
`
`670
`
`ª 2011 The Authors
`Transplant International ª 2011 European Society for Organ Transplantation 24 (2011) 666–675
`
`Ex. 1055-0005
`
`

`
`Beckebaum et al.
`
`Conversion of LT patients to once-daily tacrolimus formulation
`
`Table 3. Laboratory values during the study period.
`
`Laboratory parameter
`
`Baseline (n = 125) Month 1 (n = 123) Month 6 (n = 122) Month 9 (n = 121) Month 12 (n = 119)
`
`Leukocytes (3.6–9.2 · 109/l)
`Hemoglobin (12.0–15.2 g/dl)
`Thrombocytes (180–380 · 109/l)
`Creatinine (<1.1 mg/dl)
`Blood urea nitrogen (6–19.8 mg/dl)
`cGFR (ml/min/1.73 m2)
`Total bilirubin (0.3–1.2 mg/dl)
`AST (<35 U/l)
`ALT (<35 U/l)
`Glucose (74–109 mg/dl)
`Total cholesterol (<200 mg/dl)
`Triglycerides (<200 mg/dl)
`
`5.84 ± 2.08
`13.3 ± 1.75
`188.9 ± 101.1
`1.38 ± 0.65
`23.9 ± 11.3
`59.5 ± 20.3
`0.92 ± 1.87
`30.8 ± 26.6
`36.7 ± 37.2
`116.7 ± 49.8
`169.8 ± 42.2
`140.2 ± 87.6
`
`5.97 ± 2.13
`13.2 ± 1.66
`193.8 ± 101.5
`1.37 ± 0.63
`23.8 ± 10.4
`59.0 ± 18.6
`1.00 ± 2.46
`34.4 ± 39.1
`41.2 ± 56.4
`109.6 ± 34.9
`176.0 ± 46.2
`148.7 ± 94.8
`
`5.99 ± 2.25
`13.2 ± 1.99
`194.6 ± 98.7
`1.37 ± 0.39
`25.8 ± 16.3
`57.0 ± 16.4
`0.79 ± 0.75
`31.6 ± 23.7
`36.0 ± 31.3
`114.2 ± 44.5
`170.6 ± 41.4
`142.9 ± 93.1
`
`6.00 ± 2.25
`13.2 ± 1.99
`194.6 ± 98.7
`1.40 ± 0.55
`25.9 ± 16.2
`56.3 ± 17.1
`0.79 ± 0.75
`29.9 ± 25.5
`31.6 ± 27.2
`111.9 ± 38.2
`173.0 ± 45.1
`152.5 ± 95.2
`
`6.02 ± 2.12
`13.4 ± 1.86
`198.7 ± 99.0
`1.38 ± 0.42
`24.7 ± 11.7
`57.0 ± 18.4
`0.70 ± 0.48
`30.1 ± 21.4
`31.9 ± 24.8
`111.7 ± 36.7
`174.9 ± 44.1
`143.5 ± 98.7
`
`cGFR, calculated glomerular filtration rate; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
`
`from the TAC XL formulation because of diarrhea
`(n = 2) after 27 and 117 days, anorexia (n = 2) after 24
`and 42 days, and abdominal pain and anorexia (n = 1)
`after 231 days. Three patients were withdrawn from TAC
`OD after 8, 18, and 84 days because of fatigue, and one
`because of frequent episodes of headache (n = 1) after
`42 days.
`
`Patient reported outcomes
`
`Patients’ adherence to immunosuppressive regimen
`Overall nonadherence which was reported on at least one
`of the four queried items was 66.4% at baseline and sig-
`nificantly decreased postconversion (30.9%, P < 0.0001;
`Table 5). The most common behavior was timing nonad-
`herence with patients taking their dose with a delay of
`>2 h. Timing nonadherence decreased from baseline
`(63.6%) to month 12 (27.3%, P < 0.0001). Taking non-
`adherence decreased from 20% to 8.2% (P < 0.005),
`whereas the occurrence of drug holidays was a rare event
`overall (3.6% vs. 2.7%, P = NS). Dose reduction was
`reported by only one patient.
`Interestingly, mean VAS ratings of patient adherence
`were high at baseline (92.3 ± 8.02, range: 65–100) and
`further
`increased
`during
`follow-up
`[97.2 ± 5.1
`(P < 0.001), range: 70–100; Table 5].
`
`Patients’ preference with the treatment regimen
`Of the 110 (85.4%) patients who maintained on TAC OD
`medication throughout
`the study, 94 reported one or
`more advantages to switching to the new formulation
`[lack of
`the evening dose (n = 90),
`fewer side effects
`(n = 8),
`fewer dose changes (n = 5), and lower costs
`because of dose decrease postconversion (n = 3)] at
`month 12. There was no patient at study completion who
`preferred reconversion to TAC BID.
`
`Implication of therapeutic complexity
`on drug adherence
`At baseline, the difference in the mean number of con-
`comitant medications in nonadherent versus adherent
`patients (according to the results of the four-item vali-
`dated questionnaire) was not
`statistically
`significant
`(5.0 ± 2.7 vs. 5.1 ± 2.9, P = 0.92); the same was true at
`12 months (5.5 ± 3.2 vs. 4.9 ± 2.5, P = 0.32). We then
`categorized patients as those with a low [0–2 drugs;
`n = 23 patients (20.9%), moderate [3–5 drugs; n = 44
`patients
`(40.0%)], or
`a high number
`[>5; n = 43
`patients (39.1%)] of concomitant drugs. The differences
`in the proportion of patients with overall nonadherence
`were not
`statistically
`significant
`among
`the
`three
`subgroups,
`regardless of whether
`they were at base-
`line
`(69.6% vs. 68.2% vs. 62.8%, P = 0.81) or at
`month 12 (30.4% vs. 25.0% vs. 37.2%, P = 0.46, respec-
`tively).
`We then investigated the impact of dosing frequency
`on drug adherence. All patients had concomitant medica-
`tion in the morning. We categorized patients as those
`with once-daily (only in the morning, n = 9, 8.2%),
`twice-daily (n = 23, 20.9%) and thrice- or more than
`thrice-daily (n = 78, 70.9%) medication. We found that
`the differences in the proportion of patients with overall
`nonadherence were not statistically significant among the
`subgroups, whether at baseline (66.7% vs. 69.6% vs.
`65.4%, P = 0.93) or at month 12 (22.2% vs. 34.8% vs.
`30.8%, P = 0.78).
`
`Implication of age on drug adherence
`At study entry, the overall nonadherence rate for patients
`£60 years was significantly higher than that of patients
`>60 years (71.4% vs. 50%, P = 0.04). This difference was
`not
`statistically significant at 12 months
`(34.5% vs.
`19.2%, P = 0.14). During the study, overall nonadherence
`
`ª 2011 The Authors
`Transplant International ª 2011 European Society for Organ Transplantation 24 (2011) 666–675
`
`671
`
`Ex. 1055-0006
`
`

`
`Conversion of LT patients to once-daily tacrolimus formulation
`
`Beckebaum et al.
`
`Table 4. Adverse events during the study period.
`
`Week 1
`(n = 125)
`
`Week 2
`(n = 125)
`
`Month 1
`(n = 123)
`
`Month 3
`(n = 122)
`
`Month 6
`(n = 122)
`
`Month 9
`(n = 121)
`
`Month 12
`(n = 119)
`
`Adverse events
`
`Abdominal pain, vomiting, anorexia
`Diarrhea
`Respiratory tract infection
`Urinary tract infection
`Infections, others
`Nervous system disorders (tremor,
`paresthesia, prurigo, headache)
`Fatigue, insomnia
`Muscle pain, athralgia
`Skin and subcutaneous disorders
`(alopecia, exanthema)
`Tumor recurrence
`
`n (%)
`
`3 (2.4)
`5 (4.0)
`10 (8.0)
`1 (0.80)
`3 (2.4)
`4 (3.2)
`
`2 (1.6)
`3 (2.4)
`1 (0.80)
`
`8 (6.5)
`4 (3.2)
`5 (4.0)
`–
`4 (3.2)
`6 (4.8)
`
`7 (5.6)
`1 (0.80)
`–
`
`3 (2.4)
`6 (4.9)
`10 (8.1)
`1 (0.81)
`5 (4.1)
`5 (4.1)
`
`2 (1.6)
`3 (2.4)
`–
`
`5 (4.1)
`6 (4.9)
`4 (3.3)
`1 (0.82)
`5 (4.1)
`4 (3.3)
`
`3 (2.5)
`1 (0.82)
`1 (0.82)
`
`8 (6.6)
`4 (3.3)
`5 (4.1)
`–
`3 (2.5)
`7 (5.7)
`
`7 (5.7)
`1 (0.82)
`1 (0.82)
`
`6 (5.0)
`5 (4.1)
`5 (4.1)
`–
`6 (5.0)
`4 (3.3)
`
`5 (4.1)
`–
`2 (1.7)
`
`7 (5.9)
`5 (4.2)
`4 (3.4)
`–
`3 (2.5)
`3 (2.5)
`
`3 (2.5)
`–
`3 (2.5)
`
`–
`
`–
`
`1 (0.81)
`
`–
`
`–
`
`–
`
`–
`
`Data presented are the number and percentage of patients experienced a particular adverse event regardless of a relationship to the study drug.
`Patients may have experienced more than one adverse event.
`
`Table 5. Adherence at baseline and follow-up in patients (n = 110) maintained on once-daily tacrolimus throughout the whole study period.
`
`Baseline
`
`Follow-up (month 12)
`
`Basel Assessment of Adherence Scale
`
`n (%)
`
`Item 1: Dose not taken
`Item 2: Consecutive doses not taken
`Item 3: Dose taken with >2 h delay
`Item 4: Dose reduced
`Overall nonadherence*
`Visual Analog Scale
`
`Scale (0–100)
`
`22 (20.0)
`4 (3.6)
`70 (63.6)
`0
`73 (66.4)
`Mean
`
`92.3
`
`SD
`
`8.0
`
`Values are expressed as number (percentages) of patients.
`*Defined as any-self reported nonadherence on any of the four items.
`
`9 (8.2)
`3 (2.7)
`30 (27.3)
`1 (0.91)
`34 (30.9)
`Mean
`
`Range
`
`65–100
`
`97.2
`
`P-value
`
`<0.005
`NS
`<0.0001
`NS
`<0.0001
`
`SD
`
`5.1
`
`Range
`
`70–100
`
`<0.001
`
`rates significantly improved in patients aged £60 years
`(P < 0.001) and >60 years (P = 0.03).
`
`Implication of the time period of drug conversion on drug
`adherence
`the proportion of overall nonadherent
`At baseline,
`patients was significantly higher upon later (>2 years after
`LT) when compared with earlier conversion (71.8% vs.
`48%, P = 0.02). At 12 months, differences in the propor-
`tions of overall nonadherent patients were not statistically
`significant in both subgroups (28% vs. 31.8%, P = 0.72).
`
`Discussion
`
`This study was designed to determine the efficacy, safety,
`and PROs after conversion from TAC BID to the new
`TAC XL formulation in a cohort of stable LT recipients.
`
`In our experience with LT recipients, TAC formula
`conversion on a 1:1 mg basis was associated with lower
`TAC trough levels in nearly two-thirds of patients (>25%
`lower
`in 28.8% of patients) and increased levels
`in
`approximately one-third of patients (>25% higher in
`24.0% of patients) at week 1 postconversion. TAC con-
`centrations were approximately 10% lower at week 1
`before any dose change than at baseline, and remained
`significantly lower at week 2, prompting us to increase
`TAC doses in the corresponding patients. Moreover, TAC
`levels from 16 patients (21.1%) who were without adjunc-
`tive mycophenolate mofetil (MMF)/SRL or azathioprine
`(AZA) therapy were below the target range of 4–8 ng/ml
`(mean levels, 3.26 ± 0.6 ng/ml; range: 1.9–3.9 ng/ml) at
`week 1 postconversion. These observations suggest that
`close monitoring of target trough TAC levels is essential
`during the early postconversion period.
`
`672
`
`ª 2011 The Authors
`Transplant International ª 2011 European Society for Organ Transplantation 24 (2011) 666–675
`
`Ex. 1055-0007
`
`

`
`Beckebaum et al.
`
`Conversion of LT patients to once-daily tacrolimus formulation
`
`food
`Results from several studies have shown that
`retention in the gastrointestinal tract alters the oral bio-
`availability of TAC [15–17]. Our patients were instructed
`to administer TAC BID or TAC OD at least 1 h before,
`or two to three hours after food consumption, and to
`take their TAC OD medication 24 h before a scheduled
`blood sampling. However, the exact time period between
`TAC administration and food consumption was not doc-
`umented. Because this was not a pharmacokinetic study,
`it can only be speculated as to whether the initial decrease
`of TAC levels in two-thirds of patients upon switching to
`the OD formulation could be related to a closer time
`frame between TAC OD intake and breakfast, compared
`with TAC BID intake and food consumption in the even-
`ing. Additionally, fat meal content and circadian varia-
`tions
`in TAC absorption and disposition may be
`contributing factors for altered TAC concentrations post-
`conversion [15,18,19]. Additional studies on pharmaco-
`kinetics of TAC BID versus TAC OD oral administration
`are required for a better pharmacodynamic understanding
`of drug dosages and resulting drug concentrations.
`Higher risk of cardiovascular death and diabetes mell-
`itus in the transplant setting compared with the nontrans-
`plant setting may be largely attributed to calcineurin
`inhibitor therapy. Avoidance of high TAC peak levels
`may lead to better control of glycemic metabolism
`[20,21]. It has been shown that conversion from TAC
`BID to TAC OD regimen is associated with an equivalent
`exposure at steady state and trough levels, but with a dif-
`ferent pharmacokinetic profile with substantially reduced
`peak levels