Two cases of severe de novo colitis in kidney transplant recipients after conversion to prolonged‐release tacrolimus

Diarrhea is a frequent complication in patients after solid organ transplantation. We describe two cases of severe new onset colitis in kidney transplant recipients that developed shortly after the introduction of the therapy with prolonged‐release formulation of tacrolimus replacing standard twice daily formulation of tacrolimus in one case and cyclosporine A in the second case. Both patients developed severe, intermittent bloody diarrhea with abdominal pain, weight loss, dehydration and worsening graft function that required immediate hospitalization. The symptoms did not diminish after dose reduction or withdrawal of mycophenolic acid derivatives. After excluding bacterial, viral, fungal, and parasite infections, colonoscopy with colonic biopsy was performed in both patients, which revealed features typical of colitis. Both patients received mesalazine until the symptoms stopped. In one of the patients, standard formulation of tacrolimus was immediately reintroduced. The second patient was given everolimus in an acute phase of diarrhea. Although the two cases presented in this report cannot fully support a causal relationship between the prolonged‐release tacrolimus and colitis, they should increase awareness among transplant physicians and prompt more close monitoring of such potential side effects as a part of the pharmacovigilance plan for a new formulation of the well‐established immunosuppressive drug.     

Medication understanding,non‐adherence,and clinical outcomes among adult kidney transplant recipients

We sought to evaluate the prevalence of medication understanding and non‐adherence of entire drug regimens among kidney transplantation (KT) recipients and to examine associations of these exposures with clinical outcomes. Structured, in‐person interviews were conducted with 99 adult KT recipients between 2011 and 2012 at two transplant centers in Chicago, IL; and Atlanta, GA. Nearly, one‐quarter (24%) of participants had limited literacy as measured by the Rapid Estimate of Adult Literacy in Medicine test; patients took a mean of 10 (SD=4) medications and 32% had a medication change within the last month. On average, patients knew what 91% of their medications were for (self‐report) and demonstrated proper dosing (via observed demonstration) for 83% of medications. Overall, 35% were non‐adherent based on either self‐report or tacrolimus level. In multivariable analyses, fewer months since transplant and limited literacy were associated with non‐adherence (all P<.05). Patients with minority race, a higher number of medications, and mild cognitive impairment had significantly lower treatment knowledge scores. Non‐white race and lower income were associated with higher rates of hospitalization within a year following the interview. The identification of factors that predispose KT recipients to medication misunderstanding, non‐adherence, and hospitalization could help target appropriate self‐care interventions.     

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

The aim of this study was to determine the efficacy, safety, and immunosuppressant 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 consistent 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.     

Delayed trough level measurement with the use of prolonged‐release tacrolimus

Trough concentrations of prolonged‐release tacrolimus are usually measured at 24 h after taking the drug in the morning. It is impractical to measure these trough concentrations in patients who visit the outpatient clinic in the afternoon. Trough concentrations obtained in the afternoon may also be suitable for estimating the 24‐h exposure. We therefore aimed to assess the usefulness of tacrolimus concentrations measured at 32 h postdose for therapeutic drug monitoring in renal transplant patients who take prolonged‐release tacrolimus. We measured tacrolimus pharmacokinetics in 26 patients using prolonged‐release tacrolimus. Eleven blood samples were taken during a period of 32 h after ingestion by use of a validated dried blood spot method. Tacrolimus concentrations were measured with HPLC‐tandem mass spectrometry. The mean concentrations at 24 and 32 h postdose were 8.3 μg/l (7.5–9.1) and 6.7 μg/l (6.1–7.4), respectively (P < 0.0001). The Spearman correlation coefficients between these concentrations and 24‐h exposure were 0.83 and 0.82, respectively (both P < 0.01). In conclusion, delayed trough level measurement provides lower values and therefore requires adjustment of the target range. However, levels measured until 32 h after ingestion remain strongly correlated with 24‐h exposure. This warrants the use of delayed trough level measurement to improve patient convenience.     

LCPT once‐daily extended‐release tacrolimus tablets versus twice‐daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups

African‐American and elderly kidney transplant recipients (KTR) have increased risk for poor clinical outcomes post‐transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once‐daily formulation of tacrolimus (LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak‐trough fluctuations vs. tacrolimus twice‐daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 (LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age ≥65). Overall, treatment failure [death, graft failure, centrally read biopsy‐proven acute rejection (BPAR), or lost to follow‐up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [?1.48% (?5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [?1.29% (?5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [?13.82% (?27.22%, ?0.31%)] and KTR ≥65 [?13.46% (?25.27%, ?0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high‐risk subgroups, in particular black KTR and KTR ≥65 years old.     

Conversion to tacrolimus once-daily from ciclosporin in stable kidney transplant recipients: a multicenter study

This 24-week, open, single-arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at -10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n=42), hypertrichosis (n=106), hypertension (n=77) and gingival hyperplasia (n=76) groups. Relative change in eCrCl was -0.6% in all PPS patients (95% CI, -2.2; 0.9) and -5.3% in the hyperlipidemia (CI, -9.59; -0.97), 0.9% in the hypertrichosis (CI, -2.59; 4.45), -0.1% in the hypertension (CI, -3.8; 3.68), and -1% in the gingival hyperplasia groups (CI, -4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin-related cosmetic side effects were evident from investigator and patient self-report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin-related cosmetic side effects was observed. (ClinicalTrials.gov number: NCT00481481).     

ADHERE: randomized controlled trial comparing renal function in de novo kidney transplant recipients receiving prolonged‐release tacrolimus plus mycophenolate mofetil or sirolimus

ADHERE was a randomized, open‐label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolonged‐release tacrolimus‐based immunosuppressive regimens. On Days 0–27, patients received prolonged‐release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged‐release tacrolimus plus MMF (Arm 1) or prolonged‐release tacrolimus (≥25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full‐analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m²; P = 0.405), as were the secondary endpoints, except composite efficacy failure, which was higher in Arm 2 versus 1 (18.2% vs. 11.5%; P = 0.002) owing to a higher postrandomization withdrawal rate due to adverse events (AEs) (14.4% vs. 5.2%). Results from this study show comparable renal function between arms at Week 52, with fewer AEs leading to study discontinuation with prolonged‐release tacrolimus plus MMF (Arm 1) versus lower dose prolonged‐release tacrolimus plus sirolimus (Arm 2).     

Non‐adherence to immunosuppressive medication in renal transplant recipients within the scope of the integrative model of behavioral prediction: a cross‐sectional study

Schmid‐Mohler G, Pechula Thut M, Wüthrich RP, Denhaerynck K, De Geest S. Non‐adherence to immunosuppressive medication in renal transplant recipients within the scope of the integrative model of behavioral prediction: a cross‐sectional study.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01056.x
© 2009 John Wiley & Sons A/S. Abstract: Background: Non‐adherence to immunosuppressive medication is strongly associated with poor outcomes. Identifying the factors influencing it is a first step in developing adherence interventions. This study’s objective was to investigate the prevalence of self‐reported and collaterally‐reported non‐adherence to immunosuppressives, and, based on the Integrative Model of Behavioral Prediction, to explore the association between non‐adherence, intention to adhere, attitudes, norms and self‐efficacy. Methods: This cross‐sectional study included a convenience sample of 114 renal transplant recipients in follow‐up care, one to five yr post‐transplant. Non‐adherence was measured by self‐reports and collateral reports. Factors of the Integrative Model of Behavioral Prediction were assessed using a self‐report questionnaire. Results: Self‐reports showed non‐adherence of 23.7%; collateral reports showed 3.8%; and a combination of the two showed 26.4%. Logistic regression analysis showed that the attitude “Not all immunosuppressive drugs are necessary to prevent rejection” was less frequent in patients with higher intentions to adhere, with an odds ratio (OR) of 0.05 (95% CI 0.01–0.50). The barrier of “Forgetfulness/Interruption of daily routine” was associated with non‐adherence, with an OR of 3.74 (95% CI 1.55–9.03). Conclusions: Forgetfulness is the most powerful barrier against adherence. Intention to adhere plays a minor role in non‐adherence in renal transplant recipients.     

Tacrolimus and quality of life after kidney transplantation--a multicenter study

Kidney transplantation is currently the treatment of choice for end-stage renal disease. Although new immunosuppressive drugs have been introduced into clinical practice, the effect of such medication on quality of life (QoL) in transplant recipients is still unclear. The present study analyzes the impact of tacrolimus-based immunosuppression on QoL in a representative sample of adult kidney transplant recipients from Rio Grande do Sul, a Brazilian southern state. This was a cross-sectional multicenter study which used the SF-36 Health Survey for measuring QoL. The effect of tacrolimus on QoL was adjusted for possible confounders using multiple linear regression. A total of 272 patients (from 11 different centers) were evaluated, 48 of them were treated with tacrolimus. Transplant patients in use of tacrolimus presented significant higher scores in the physical component summary of SF-36 than non-users (49.1+/-8.3 vs. 46.1+/-8.7; p=0.03), and such difference was noted in the physical functioning and general health subscales (81.5+/-17.1 and 74.7+/-21.8; 74.6+/-22.3 and 67.1+/-22.3 for users and non-users of tacrolimus, respectively, p<0.05). The effect of tacrolimus remained significant after adjustment for age, gender, skin color and time since transplantation (coeff.: 2.83; 95% CI: 0.05-5.6, p=0.045). The association between tacrolimus-based immunosuppression and better perception of physical functioning and general health for renal transplant patients represents a significant finding as it may influence therapeutical decisions and contribute to maximize kidney transplantation benefits.     

Randomized trial of early corticosteroid reduction vs. regular‐dose corticosteroid maintenance in combination with tacrolimus and mycophenolate mofetil in living donor kidney transplant recipients: the Brazilian CORRETA trial

Garcia VD, Carvalho DBM, Gonçalves RT, Cavalcanti RL, Campos HH, Abbud‐Filho M, Lobao‐Neto AA. Randomized trial of early corticosteroid reduction vs. regular‐dose corticosteroid maintenance in combination with tacrolimus and mycophenolate mofetil in living donor kidney transplant recipients: the Brazilian CORRETA trial.
Clin Transplant 2010: 24: E109–E115.
© 2009 John Wiley & Sons A/S. Abstract: This multicenter, randomized trial aimed to compare the safety and efficacy of an early reduction in corticosteroid dose vs. long‐term maintenance in Brazilian patients on an immunosuppressive regimen based on tacrolimus and mycophenolate mofetil (MMF). In the control arm, prednisone was progressively reduced from days 8 to 90 and then kept for 12 months. In the experimental arm, prednisone was given for 12 months at the dose of 5 mg every other day. Endpoints were the composite occurrence of death, graft loss, or Banff III acute rejection, and safety. A total of 83 patients were enrolled, and 77 were analyzed for efficacy safety. One death occurred in each group. There were no cases of graft loss and one case of grade 3 acute rejection in the early reduction arm. There was no difference in the rate of the composite primary endpoint between both arms (p = 0.215), and there were no significant differences between both arms in terms of adverse events. Except for higher incidence of hypertriglyceridemia levels among patients in the regular‐dose arm, there were no significant differences between both arms in terms of adverse events. The results of this trial suggest that early reduction of corticosteroid can be feasible and safe within a timeframe of 12 months in patients receiving tacrolimus and MMF.     

Once‐daily,prolonged‐release tacrolimus vs twice‐daily,immediate‐release tacrolimus in de novo living‐donor liver transplantation: A Phase 4, randomized,open‐label,comparative, single‐center study

Randomized, open‐label, comparative, single‐center, Phase 4, 24‐week study comparing pharmacokinetics (PK), safety, and efficacy of once‐daily, prolonged‐release tacrolimus (PR‐T) with twice‐daily, immediate‐release tacrolimus (IR‐T) in adult de novo living‐donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR‐T or IR‐T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration‐time curve over 24 hour (AUC_0‐24). Predefined similarity interval for confidence intervals of ratios: 80%‐125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C₂₄), patient/graft survival, biopsy‐confirmed acute rejection (BCAR), treatment‐emergent adverse events (TEAEs). One‐hundred patients were included (PR‐T, n = 50; IR‐T, n = 50). Compared with IR‐T, 40% and 66% higher mean PR‐T daily doses resulted in similar AUC_0‐24 between formulations on Day 6 (PR‐T:IR‐T ratio of means 96.8%), and numerically higher AUC_0‐24 with PR‐T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC_0‐24 and C₂₄, and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR‐T vs IR‐T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR‐T was efficacious; no new safety signals were detected.     

Conversion from twice‐daily to once‐daily tacrolimus formulation in pediatric liver transplant recipients – a long‐term prospective study

To assess the safety and efficacy of conversion from twice‐daily tacrolimus to once‐daily tacrolimus in pediatric liver transplant recipients. Conversion from twice‐daily to once‐daily tacrolimus was made in stable pediatric liver transplant recipients. Doses and serum levels of tacrolimus, liver, and renal function were recorded on the day before the conversion and at days 5, 30, 90, and 180 postconversion. Patients were controlled every 2–3 months thereafter. Fifty‐five patients were enrolled in the study. The mean age at conversion was 10.2 ± 3.6 years. The mean tacrolimus trough level was 4.7 ± 1.9 ng/dl preconversion, followed by a significant decline to 4.2 ± 1.7 30 days after the switch (P < 0.004). Mean daily tacrolimus dose was 0.09 ± 0.046 mg/Kg preconversion with a significant increase to 0.11 ± 0.060 3 months postconversion (P < 0.001). Fifteen patients with calculated glomerular filtration rate between 60 to 80 ml/min/m² preconversion showed a significant improvement one and 3 years after the switch (73 ± 4.1, 83 ± 4.3 and 90.3 ± 7.3 ml/min/m², respectively (P < 0.001). The mean follow‐up was 5.2 ± 2.4 years. Conversion to once‐daily tacrolimus is safe and effective in a cohort of stable pediatric liver transplant patients.