Efficacy and Safety of Conversion from Twice-daily to Once-daily Tacrolimus in a Large Cohort of Stable Kidney Transplant Recipients

Authors


Luís Guirado, lguirado@fundacio-puigvert.es

Abstract

Prolonged-release tacrolimus was developed to provide a more convenient once-daily dosing that could improve patient adherence. We conducted a multicenter, prospective, observational, 12-month study to describe the efficacy, safety and patient preference of conversion from tacrolimus twice-daily to once-daily formulation in stable kidney transplant recipients in routine clinical practice. Conversion was made on a 1 mg: 1 mg basis (1 mg: 1.1 mg in patients with trough levels <6 ng/mL). The study included 1832 patients (mean age (±SD): 50.0 ± 13.4 years; 62.7% male). After conversion, a modest reduction in tacrolimus trough levels, necessitating an increase in daily dose, was observed (mean changes at 12 months of –9.1% and +1.24%, respectively; p < 0.0001). Mean glomerular filtration rate did not change significantly (56.5 ± 19.7 mL/min at conversion vs. 55.7 ± 20.6 mL/min at 12 months). Proteinuria, blood pressure, lipid, hepatic and glucose parameters remained stable. Eight patients (0.4%) had acute rejection and 34 patients (1.85%) discontinued treatment. Almost all patients (99.4%) preferred the once-daily formulation, because of less frequent dosing (66%) and improved adherence (34%). In conclusion, at similar doses to twice-daily tacrolimus, once-daily formulation provided stable renal function, a low acute rejection rate, and good tolerability in stable kidney transplant recipients in the routine clinical practice setting.

Abbreviations: 
AE

adverse event

ALT

alanine aminotrasferase

AUC0-24

24-h area under the curve

CI

confidence interval

Cmin

whole blood trough concentration

ICH

International Conference for Harmonisation

GCP

good clinical practices

GFR

glomerular filtration rate

HDL

high density lipoprotein

LDL

low density lipoprotein

MDRD

Modification of Diet in Renal Disease Study

MMF

mycophenolate mofetil

MPS

sodium mycophenolate

mTOR

mammalian target of rapamycin

PK

pharmacokinetic

SD

standard deviation

Introduction

Despite advances in immunosuppressive therapy, noncompliance to treatment remains a major problem in kidney transplantation that leads to increased rejection and graft loss (1). The risk of noncompliance increases when the immunosuppressive regimen involves frequent dosing, multiple drugs and dosage frequencies, or unexpected drug side effects (1). Furthermore, adherence seems to be significantly lower for the evening versus the morning dose (2).

The new prolonged-release formulation of tacrolimus (Advagraf®; Astellas Pharma Inc., Tokyo, Japan), available since 2007 in Europe, in several countries in South America, and in Japan and Korea, was developed to provide a more convenient once-daily dosing that could improve patient adherence. In clinical studies, once-daily tacrolimus demonstrated a pharmacokinetic (PK), efficacy and safety profile comparable to twice-daily tacrolimus (Prograf®; Astellas Pharma Inc., Tokyo, Japan) (3–6). For the standard-release formulation, total drug exposure over a dosing interval (24-h area under the curve [AUC0–24]) and whole blood trough concentration (Cmin) are the best predictors of acute rejection (AR) risk and adverse events (AEs) (7,8). The PK study by Hardinger et al. reported that standard-release tacrolimus given once daily at 85% of the twice daily dose provided bioequivalent drug exposure to the twice-daily dosing and that the 24-h trough concentration was a good marker for total tacrolimus exposure (9). Phase I studies involving healthy volunteers demonstrated that prolonged-release tacrolimus’ AUC0–24 was bioequivalent according to FDA/EMEA criteria (90% CI geometric mean Cmin preconversion/Cmin postconversion within 80–125% range), had a similar correlation of Cmin to AUC0–24; same trough target ranges; and 1: 1 (mg: mg) conversion to that of standard-release tacrolimus (3). Several conversion studies have demonstrated bioequivalence (10% lower systemic steady-state exposure, comparable trough minimal concentrations, and slightly reduced peak levels) (10) between the two formulations, allowing 1: 1 (mg: mg) conversion in stable kidney transplant recipients previously treated with twice-daily tacrolimus regardless of gender, race or presence of diabetes (4,11) with a comparable safety profile at 2-year follow-up (12). As stated by the manufacturer, conversion to the once-daily prolonged-release formulation on a 1: 1 (mg: mg) total daily dose basis in stable kidney transplant recipients can result in 10% lower systemic exposure to tacrolimus; highlighting the need to closely monitor tacrolimus trough levels, adjusting, if necessary, the dose (10%) in order to maintain the adequate systemic exposure (11,13–15).

Since the marketing of once-daily tacrolimus, few studies in small cohorts of stable kidney transplant recipients have reported the experience in clinical practice with the conversion to the new formulation as maintenance immunosuppression (13–17). However, large multicentric studies assessing the detailed evolution of efficacy and safety of conversion to prolonged-release tacrolimus in routine clinical practice are lacking. Thus, the objective of the present observational study was to describe efficacy of once-daily prolonged-release formulation in terms of patient and graft survival in a large cohort of stable kidney recipients converted from twice-daily tacrolimus in routine clinical practice.

Materials and Methods

The EVOLUTION study (Evaluation of Advagraf Conversion and Long-Term Use in Kidney Transplantation) was a multicenter, prospective, observational study that was conducted by the Spanish Group of new clinical projects in transplantation (GREAT) in the routine clinical practice of 21 Spanish hospitals from September 2007 to March 2010. The Local Ethics Committee of each center approved the protocol and all patients gave written informed consent before inclusion. The study procedures were in accordance with the ICH/GCP guidelines and the ethical standards of Helsinki Declaration. All adult stable kidney transplant recipients who were converted from tacrolimus twice-daily to a once-daily prolonged release formulation in the routine clinical practice during the recruitment period (between September 2007 and March 2009) were eligible for the study. Stable patients were defined as those without an acute rejections episode and without an increase >10% in serum creatinine in the last 12 months. Patients who were not stable or considered to be at immunologic risk were excluded from the study.

Before conversion all patients were treated with twice-daily standard-release tacrolimus, combined with prednisone, plus an antimetabolite or an mTOR inhibitor, according to local clinical practice. The conversion to once-daily prolonged-release tacrolimus was performed on a 1 mg: 1 mg or 1 mg: 1.1 mg (total daily dose) basis. The latter conversion strategy was used in patients with baseline levels of tacrolimus of ∼6 ng/mL, in order to avoid levels <6 ng/mL after conversion. Thereafter, doses were adjusted to maintain target whole blood trough levels between 6–15 ng/mL. Tacrolimus blood concentration were measured with a total blood heterogeneous electrochemical luminescence immunoassay (Dimension Siemens). Patient visits occurred 14, 30, 60 and 90 days postconversion and every 3 months thereafter. When dose adjustments were necessary, a patient visit occurred 14 days postadjustment. Patients were maintained on their original immunosuppressive regimen unless medical needs required a change in medication. Because a fatty meal reduces tacrolimus oral bioavailability (18) and adsorption is remarkably better in the morning (9), prolonged-release tacrolimus was administered once-daily in the morning at 8 a.m., at least 1 h before eating anything. Compliance was assessed at each visit by asking the patients whether there had been any deviations from the medication schedule.

Patients were followed for 12 months after conversion, unless they lost the graft. Clinical status (body weight, blood pressure) and laboratory parameters (serum creatinine, proteinuria, alanine aminotrasferase [ALT], glycemia, glycosilated haemoglobin, triglycerides, total cholesterol, high density lipoprotein [HDL] cholesterol, low density lipoprotein [LDL] cholesterol and haemoglobin) were monitored at conversion and 14 days after conversion, and at 1, 3, 6, 9 and 12 months. Serum creatinine levels at 6 and 12 months prior to conversion were also collected. Other immunosuppressive treatments, concomitant treatments and episodes of acute rejection were also recorded. At each visit patients were asked to describe any new AEs experienced with once-daily tacrolimus; any increases in tremors or neurotoxicity symptoms were recorded to monitor tacrolimus neurotoxicity.

The main endpoints of the study were patient and graft survival. Secondary endpoints included: renal function measured by glomerular filtration rate (GFR), which was estimated from serum creatinine using the Modification of Diet in Renal Disease Study (MDRD-4) equation, episodes of biopsy-proven acute rejection, evolution of serum creatinine and proteinuria, blood pressure, lipid, glucose and liver parameters and AEs. Patient preference was also evaluated with two questions: (1) What is your personal feeling after your conversion from Prograf® to Advagraf®? (positive/negative); (2) If the answer to the first question is ‘positive’, reasons for your positive impression (increased convenience with not having an evening medication intake/improved adherence to medication).

All statistical analyses were performed using the SPSS statistical package version 15.0 (SPSS Inc., Chicago, IL, USA). Categorical variables were described using frequency tables and percentages, and continuous variables using measures of central tendency and dispersion (mean, SD or median, range). Analyses were based on observed data only. Paired Student's t-tests or Wilcoxon signed-rank tests as appropriate were applied to evaluate differences in mean values between conversion and 6 or 12-month visits, and McNemar tests were used to evaluate differences in qualitative variables. For analysis of graft and patient survival, Kaplan Meier estimates were obtained. Statistical significance was defined as p values less than 0.05. All p values were two-sided.

Results

The study included 1832 renal transplant recipients (62.7% male), transplanted between 1985 and 2008, who were converted to once-daily tacrolimus in routine clinical practice. The mean (±SD) age was 50.0 ± 13.4 years (range 18–80). The mean (±SD) time from transplantation to conversion was 1838 ± 1450 days.

Conversion was made on a 1 mg: 1 mg basis in 96.0% of patients, and on a 1 mg: 1.1 mg basis in the remaining 4.0%. Mean tacrolimus dose and trough levels at conversion were 4.01 ± 2.45 mg/day and 7.49 ± 2.81 ng/mL, respectively. A statistically significant reduction in blood levels, necessitating an increase in daily dose, was observed at the 14-day visit (Figure 1). The mean change at 6 months was –11.5% for blood levels and +0.75% for daily dose (p < 0.0001 versus conversion in both cases), and at 12 months was –9.1% and +1.24%, respectively (p < 0.0001 versus conversion in both cases).

Figure 1.

Evolution of tacrolimus doses and blood trough levels during the 12 months after conversion from twice-daily tacrolimus to once-daily prolonged-release formulation in routine clinical practice (n = 1832).

Before conversion, 66.5% of patients were concomitantly treated with prednisone (mean dose of 5.6 ± 2.9 mg/day), 78.4% with an antimetabolite (60.9% with mycophenolate mofetil [MMF] and 17.5% with sodium mycophenolate [MPS]) and 3.3% with an mTOR inhibitor. At 12 months postconversion, no relevant changes were observed in concomitant immunosuppressive agents, except for a reduction in prednisone doses: 58.2% of patients were receiving prednisone (mean dose of 5.0 ± 1.6 mg/day, p < 0.0001 versus conversion), 77.6% were receiving an antimetabolite (59.4% with MMF and 18.2% with MPS) and 2.6% were receiving an mTOR inhibitor.

Excellent graft and patient survival were observed at 1 year (99.8%). Only 8 of the 1832 patients (0.4%) had biopsy-proven acute rejection, which could not be attributed to noncompliance or low blood levels of tacrolimus (Table 1). Four patients (0.2%) died during the 12-month study: 1 respiratory insufficiency at 6 months postconversion, 2 neoplasias at 6 and 12 months postconversion and 1 death during lower limb revascularization surgery at 10 months postconversion; all unrelated to immunosuppression conversion. Apart from the 4 graft losses due to patient death, no other graft was lost. Study discontinuations in 30 additional patients (1.64%) occurred because of new onset neurologic alterations in 8 patients (0.4%), low blood trough levels after conversion in 8 patients (0.4%), tacrolimus-related nephrotoxicity in 3 patients (0.2%), diarrhea in 3 patients (0.2%), new onset diabetes mellitus in 1 patient (0.05%), polyomavirus infection in 2 patients (0.1%) and neoplasia in 5 patients (0.3%). Patients were either converted back to twice-daily tacrolimus or to an mTOR inhibitor without complications.

Table 1.  Biopsy-proven acute rejection (BPAR) episodes after conversion from twice-daily tacrolimus to once-daily prolonged-release formulation in routine clinical practice (n = 1832)
PatientTacrolimus blood levels (ng/mL)Time from transplant to BPAR (days)Time from conversion to BPAR (days)Banff 07 grade
  1. BPAR = biopsy-proven acute rejection; TMCR = T-cell mediated rejection; CAAMR = chronic active antibody-mediated rejection; IFTA = interstitial fibrosis and tubular atrophy.

16.01031170TCMR IA
27.5 857289TCMR IA
38.82367286TMCR IIA
45.47642378CAAMR C4d+
56.74811386CAAMR C4d+, IFTA I
65.54733394CAAMR C4d+
75.1 474464TCMR IA
88.9 481298TCMR IA, IFTA I

Mean serum creatinine showed a trend toward reduction in the 12 months prior to conversion (Figure 2). Thereafter, a statistically significant, but not clinically relevant increase was observed at 3, 6 and 12 months postconversion (Figure 2). However, mean GFR values did not change significantly during follow-up (56.46 ± 19.7 mL/min at conversion versus 55.7 ± 20.6 mL/min at 12 months, Figure 3). In addition, no significant changes were observed in other clinical and biochemical parameters at the end of study, including proteinuria (Table 2). Three patients reported calcineurin–inhibitor-related nephrotoxicity during follow up. Finally, no changes were observed in antihypertensive, hypoglycaemic or hypolipemiant use between conversion and the 12-months visit: mean number of antihypertensives of 1.35 ± 1.13 versus 1.44 ± 1.16, respectively; 12.3% of patients with insulin and 4.9% with oral antidiabetics versus 11.6% and 5.3%, respectively; 43.9% of patients with statins versus 46.9%.

Figure 2.

Evolution of serum creatinine in the 12 months prior to conversion and in the succeeding 12 months (n = 1832).

Figure 3.

Evolution of glomerular filtration rate (MDRD) in the 12 months after conversion from twice-daily tacrolimus to once-daily prolonged-release formulation in routine clinical practice (n = 1832).

Table 2.  Evolution of clinical and laboratory parameters in the 12 months after conversion from twice-daily tacrolimus to once-daily prolonged-release formulation in routine clinical practice (n = 1832)
Parameter (mean)Conversion14 days3 months6 months12 months
  1. SBP = systolic blood pressure; DBP = diastolic blood pressure; ALT = alanine aminotransferase; LDL = low density lipoprotein; HDL = high density lipoprotein.

Proteinuria (g/24 h)0.310.290.310.350.34
Hemoglobin (g/L)135.8135.8136.0136.1136
SBP (mmHg)133.5133.1133.4133.0133.2
DBP (mmHg)76.075.976.876.776.6
Cholesterol (mmol/L)4.804.794.824.814.80
LDL cholesterol (mmol/L)2.772.752.812.842.80
HDL cholesterol (mmol/L)1.351.341.321.291.35
Triglycerides (mmol/L)1.631.591.551.571.61
Glucose (mmol/L)5.835.895.915.935.90
Glycosilated hemoglobin (%)5.66.15.75.75.7
ALT (U/L)22.922.122.621.722.1

Patients expressed a clear preference for once-daily tacrolimus (99.4% of positive feeling after conversion), because of the increased convenience of less frequent administration in 66% of patients and because of improved adherence in the remaining 34%.

Discussion

The present study is the first describing the Spanish experience with a large cohort of stable renal transplant patients converted from twice-daily standard-release tacrolimus to a once-daily prolonged-release formulation in routine clinical practice. Our results suggest that the conversion on a 1 mg: 1 mg basis is efficacious and safe, and allows to maintain stable renal function, as indicated by the absence of change in GFR and proteinuria. Accordingly, an excellent patient and graft survival were also observed. These results are consistent with the trials performed in the clinical development plan of prolonged-release tacrolimus, which demonstrated that it maintains the renal function after conversion from standard-release formulation, with the advantage of once-daily administration (3–5).

In our study, we found that extended-release tacrolimus could be monitored and handled in a similar manner compared to standard-release tacrolimus with small increases in the dose requirements (less than 3% of relative increase in the entire sample) at the time of conversion to a once-daily formulation because of modest reductions (of approximately 10%) in tacrolimus levels during the first days of administration after conversion. Thereafter, the levels and doses remained stable for the rest of the year. Several studies have shown that once-daily prolonged-release tacrolimus has comparable exposure to twice-daily formulation in the steady state, good correlation of Cmin and AUC0–24, and the same range of target levels for therapeutic purposes, indicating that the same therapeutic monitoring system can be used both formulations (3–5). However, prolonged-release tacrolimus gives a slightly lower Cmax and AUC than twice-daily standard-release tacrolimus, with less diurnal variation in drug levels (3–5). According to label recommendations, kidney transplant patients may be converted from twice-daily tacrolimus to a once-daily prolonged-release formulation on a 1: 1 (mg: mg) total daily dose basis, but following conversion, dose adjustments may be required to maintain comparable drug exposure (5 to 15 ng/mL in maintenance therapy) (11). The levels reported in our study were in the lower part of the recommended range, probably because the study population consisted mainly of low-risk patients (PRA <10% at transplantation, no acute rejection episodes in >12 months, no previous graft loss for immunologic reasons) in whom calcineurin inhibitors were maintained as low as possible to prevent nephrotoxicity. Nevertheless, the low acute rejection rate suggests that the degree of immunosuppression was sufficient to avoid rejection, and comparable to that achieved with similar doses of standard-release tacrolimus. Previous observational studies in renal recipients have also reported a modest increase in dose requirements after conversion from the standard-release tacrolimus to the prolonged-release formulation (13–16). Diez Ojea et al. found that, among 82 stable renal transplant recipients converted to once-daily tacrolimus on a 1 mg: 1 mg basis, 7.6% required a dose adjustment (16). However, after an initial decrease in trough levels at day 7, no additional changes were observed during 3 months of follow-up. Renal function remained stable and no episodes of acute rejection were described. The mean trough levels were very similar to ours (5.8 ng/mL at 3 months postconversion), probably due to a comparable clinical profile between the two cohorts. Three recent studies have also reported the need to carefully monitor renal transplant recipients during conversion to once-daily prolonged-release tacrolimus adjusting the dose requirements in a subset of patients to maintain comparable drug exposure; there were no reports of acute rejection episodes (13–15).

Despite these findings about small increases in dose requirements with once-daily tacrolimus in the clinical practice, a recent analysis that modeled patient outcomes and treatment costs for renal transplant patients over 5 years, found that prolonged-release tacrolimus could provide an average cost saving of $9411 per patient, due to improved adherence. In that model, an absolute increase of 6.1% in graft survival at 5 years was estimated for patients using once-daily tacrolimus plus MMF with respect to twice-daily tacrolimus plus MMF (19). Well-designed studies with objective measures of adherence to once-daily tacrolimus that measure clinical and economic outcomes are needed in the future to confirm these benefits (3).

The overall tolerability profile of once-daily tacrolimus appears to be similar to that of standard tacrolimus in de novo and stable renal and liver transplant patients (10). In our cohort, no changes in blood pressure, lipid and hepatic profiles, or glucose parameters (except one case of diabetes mellitus) were observed. The number of treatment discontinuations was extremely low. No cases of severe new onset colitis (a rare AE recently reported in two renal recipients shortly after the introduction of prolonged-release tacrolimus (20)) were reported.

In our study, there are certain limitations inherent to the observational, nonrandomized design that should be taken into account, such as the absence of a control group. A full PK analysis of the data was not performed because the study was carried out collecting the details of tacrolimus conversion according to the local clinical practice of each participating center. As mentioned earlier, several studies have described the safety and PK bioequivalency of the twice-daily standard-release formulation and the once-daily prolonged-release formulation of tacrolimus as long as the levels of tacrolimus are adequately monitored, in order to avoid unexpected efficacy and safety concerns (3–5,11–15). We did not collect detailed data about doses or levels of other immunosuppressive agents during the follow-up, and thus we cannot discard the existence of temporary increases that could have balanced the modest reduction in tacrolimus doses. In the analysis of renal function, we did not control for potential confounders as comorbidities. We did not collect an objective measure of adherence with the new formulation, either, only a subjective, one-item measure of patient preference. However, our study provides information about the use of prolonged-release tacrolimus in routine clinical practice in a large number of patients of different profiles with a long-term follow-up, in contrast to previous observational studies or clinical trials. To our knowledge this is the largest observational study assessing the safety and efficacy of conversion from twice-daily standard-release tacrolimus to once-daily prolonged-release tacrolimus in maintenance kidney transplant recipients (Table 3). In conclusion, once-daily prolonged-release tacrolimus provided efficacy and safety similar to twice-daily standard-release tacrolimus in a large cohort of stable kidney transplant recipients in routine clinical practice in Spain. At similar doses of twice-daily tacrolimus, once-daily prolonged-release formulation provided a stable renal function, a low acute rejection rate and good tolerability.

Table 3.  Conversion studies from twice-daily standard-release tacrolimus to once-daily prolonged-release tacrolimus in maintenance kidney transplant recipients
Study durationNConversion dose Mean dose1Side effects of once-daily tacrolimusOutcome
BPARSurvival
  1. 1At study end. NR, not reported; BPAR = biopsy-proven acute rejection.

American Phase Study II
 35 days (4)671 mg: 1 mg
6.1 ± 3.5 mg
AE profile consistent with that of twice-daily tacrolimusNo BPAR 
 2 years (12)591 mg: 1 mg 6.0 ± 3.4 mgAE profile consistent with that of twice-daily tacrolimus  Cellulitis (4.5%)  Acute renal failure (4.5%)  Human poliomavirus (3%)  Pyelonephritis (3%)  Urinary tract infection (3%)  Blood creatinine increased (3%)6% (4 of 67 pts)Patient survival: 100% Graft survival: 98.5%
European Phase Study II
 56 days (21)691 mg: 1 mg NRComparable safety profile to twice-daily tacrolimusNo BPAR 
 2 years (22)591 mg: 1 mg NRBlood creatinine increased Dizziness Skin carcinomaNo BPARPatient survival: 95, 4% Graft survival: 95, 4%
S. Africa and Netherlands
 4 years (23)671 mg: 1 mg 5.3 mg (0.07 mg/kg)Infections (34, 3%) Metabolism and nutrition disorders (25, 4%) Neoplasms benign, malignant and unspecified (10, 4%)No BPARPatient survival: 93, 6% Graft survival: 92, 2%
European Phase Study IIIb
 1 year (24)1141 mg: 1 mg 0.07 ± 0.03 mg/kgInfections (12, 1%) Metabolic disorders (2, 6%) Hypertension (4, 3%)No BPARPatient survival: 100% Graft survival: 100%
Spain
 3 months (16)661 mg: 1 mg 3.7 ± 2.1 mgTolerance similar to that of standard tacrolimusNo BPAR 
 3 months (25)381 mg: 1 mg 2.45 ± 1.67 mgNo significant differences versus standard tacrolimusNo BPAR 
Belgium
 6 months (14)550.081 mg/kgCreatinine values remained stable over timeNo acute rejection 
Italy
 6 months (15)201 mg: 1 mg Range 1.5–5.5 mgGlycemia and triglycerides showed significant reductions after conversionNo BPAR 

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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