Reports

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PRIORITY PRESS - American Transplant Congress 2009

Boston, Massachusetts / May 30-June 3, 2009

Until now, the long-term effects of the two calcineurin inhibitors (CNIs) on renal function have not been known and most CNI minimization studies do not differentiate between the two CNIs. However, as suggested by Dr. Nagappan Kumar, University Hospital of Wales, Cardiff, both laboratory and clinical studies have demonstrated that cyclosporine (CsA) is more nephrotoxic than tacrolimus. The aim of the current study was therefore to assess the long-term effect of the two CNIs on renal function, graft and patient survival and the development of new-onset diabetes after transplantation (NODAT).

The original comparative trial was completed in 2001 and investigators followed up all 150 patients - 76 in the CsA microemulsion group and 74 in the tacrolimus group - until October 31, 2008. At a mean follow-up of 9.6 years, 64% of patients on tacrolimus still had a functioning graft compared with 54% of the CsA cohort. The estimated glomerular filtration rate (eGFR - Cockroft-Gault formula) was 55 mL/min/1.73 m2 in the tacrolimus group vs. 40 mL/min/1.73 m2 in the CsA cohort (P=0.002).

“A higher proportion of patients in the tacrolimus group were also rejection-free at 10 years - 63% vs. 42% (P=0.01),” Dr. Kumar added. The one variable that was not in favour of tacrolimus was the incidence of NODAT, which at 23% was significantly higher than the 5% incidence seen in the CsA group at 10 years (P=0.002), he noted. He added that over 10 years of follow-up, 22 patients in the CsA arm were converted to tacrolimus, while four patients on tacrolimus were converted to CsA.

“Based on our data, we feel that CNI trials should not consider tacrolimus and CsA together but should be reported as CsA minimization and tacrolimus minimization,” Dr. Kumar concluded.

Extended-release Formulation

Studies evaluating the efficacy of once-daily (q.d.) extended-release (ER) tacrolimus indicate that the regimen is as safe and effective as the twice-daily CNI but has the added convenience of being given as a single daily dose in the morning. As was pointed out by investigators here, between 7% and 21% of solid organ transplant recipients develop chronic renal failure five years after transplantation and non-compliance has been shown to increase late graft loss, especially in young adults.

In evaluating four cohorts of patients who had participated in q.d. tacrolimus phase II trials, Dr. Rita Alloway, Director, Transplant Clinic, University of Cincinnati, Ohio, and colleagues prospectively followed two de novo cohorts (one kidney, one liver) who received q.d. tacrolimus immediately after transplantation and two stable conversion cohorts—one kidney, one heart—who were switched from tacrolimus b.i.d. to q.d. tacrolimus.

Roughly three-quarters of all patients completed the 48-month follow-up. “Patient and graft survival estimates exceeded 90% at four years’ follow-up in all cohorts,” Dr. Alloway reported. Other findings were as follows:

Table 1. Efficacy and Renal Function at 48 Months

She told delegates, “Tacrolimus q.d. is more convenient for patients and a simple dosing regimen over time may have potential adherence benefits that could improve overall graft survival.”

The once-daily formulation was also assessed in a separate cohort of liver transplant recipients, all of whom had completed 12 months of a phase III European study in which they received either q.d. or b.i.d. tacrolimus. Following study completion, they were enrolled in a single-arm q.d. tacrolimus prospective study and 119 out of 130 patients completed the second year of follow-up.

As reported by Dr. Pavel Trunecka, IKEM, Prague, Czech Republic, the mean daily dose of q.d. tacrolimus ranged from 0.066 mg/kg at the start of the study to 0.059 mg/kg closer to study end point. “Trough levels were between 6 and 8 ng/mL,” Dr. Trunecka noted, adding that these levels were “probably appropriate” for tacrolimus monotherapy. Indeed, 70% of patients were maintained on q.d. tacrolimus maintenance therapy through to 24 months, he added. One patient died during follow-up and there were five episodes of acute rejection—four being very mild—and no graft loss due to rejection. “Kidney function was excellent during the trial,” Dr. Trunecka remarked.

At the end of the randomized controlled trial (12 months), mean serum creatinine was 109.3 mmol/L and levels remained stable through to month 24, when the mean serum creatinine was 108.4 mmol/L. Similarly, mean creatinine clearance at month 12 was 76 mL/min/1.73 m2 and there was very little fluctuation in levels through to month 24 when the mean creatinine clearance was 77.9 mL/min/1.73 m2.

“These results are fully compatible with any study for tacrolimus twice-daily, and the most important finding was that the majority of liver transplant patients can be maintained on ER tacrolimus administered once a day,” Dr. Trunecka concluded.

Enhancing Adherence

Study findings indicate that non-adherence has been reported in up to 55% of kidney transplant recipients and is one of the major causes of preventable graft loss (Chisolm MA. Drugs 2002;62:567-75). Conversely, a q.d. immunosuppressive regimen, with the single dose taken in the morning, has been associated with a greater likelihood of adherence compared with twice-daily dosing.

The efficacy of q.d. tacrolimus was further evaluated in a year-long follow-up of another phase III study in kidney transplant recipients treated with q.d. tacrolimus for a mean of 18 months. Approximately 93% of patients who completed the phase III study also completed the one-year follow-up study. Out of 177 patients who entered the follow-up study, 14 withdrew for various reasons, as noted by co-investigator Dr. Bernhard Krämer, Professor of Medicine, University of Bochum, Germany.

At one-year follow-up, 59.2% of patients were receiving once-daily tacrolimus, corticosteroids and mycophenolate mofetil (MMF); 25.7% were receiving q.d. tacrolimus plus MMF and 5.2% were receiving q.d. tacrolimus and corticosteroids. The mean daily dose of tacrolimus decreased from 0.84 mg/kg during months 1 to 3 to a mean daily dose of 0.076 mg/kg between months 10 and 12. Whole body trough levels remained stable over the one-year follow-up at a mean trough level of 7.8 ng/mL.

At one-year follow-up, graft survival rates were excellent at 98.9% while 100% of patients were still alive. Biopsy-proven acute rejection (BPAR) occurred in only a single patient for a freedom-from-BPAR rate of 99.5% at one year, while chronic rejection occurred in two patients. “Renal function as measured by serum creatinine and creatinine clearance remained stable throughout the one-year follow-up,” Dr. Krämer added. Renal function is considered a better predictor of long-term patient and graft survival than acute rejection, as has been recently recognized.

Among the more common adverse events were gastrointestinal disorders (11.5%), infections (17.8%) and metabolism and nutrition disorders (28.3%). Hyperglycemia occurred in 6% of patients with pre-existing glucose metabolism disorder; another 6% developed non-insulin-dependent diabetes and 4.2% developed insulin-dependent diabetes. Benign neoplasms and malignancies occurred very infrequently.

“These follow-up data confirm the long-term safety and efficacy of a simplified once-daily tacrolimus regimen in kidney transplant recipients,” the authors concluded, “and results from this study are similar to those expected with tacrolimus taken twice a day.”