Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

13th Congress of the European Society for Organ Transplantation

Prague, Czech Republic / September 29-October 3, 2007

“In our literature review, we found that 40% to 60% of all late acute rejections are due to non-adherence,” stated Dr. Fabienne Dobbels, Catholic University of Leuven, Belgium. “The incidence of late acute rejection in the long term after transplantation is <10%, but when it occurs, it is due to non-adherence in half of the cases. Non-adherence is often not the only cause, but it is a commonly overlooked variable when explaining poor results. Similarly, up to 20% of graft losses or late death are due to non-adherence.”

She told the audience, “Even among patients who were facing death prior to transplantation, we found that 20% to 30% of them were non-adherent to their post-transplant immunosuppressive regimen.” It has been observed that some patients decrease their adherence even while being monitored for it.

Standard vs. Simplified Immunosuppression Regimens

Dr. Rutger Ploeg, Groningen University, The Netherlands, and ESOT Secretary General, suggested that once-daily dosing with prolonged-release tacrolimus capsules is an important step forward in addressing the growing concern of non-adherence. Compared with twice-daily dosing, once-daily medication more than doubles the likelihood of patients taking treatment as prescribed. Prolonged-release tacrolimus is the first calcineurin inhibitor specifically tailored for once-daily administration. It provides pharmacokinetic, safety and efficacy profiles comparable to those of the classic standard b.i.d. formulation.

“We are now using very complex drug regimens for each patient,” noted Dr. Ploeg. “One of the pitfalls of these very sophisticated protocols is that there is a substantially higher chance of patient non-adherence. Research suggests that 20% to 50% of organ transplant patients fail to take their medications correctly, and missing just a few doses of cornerstone immunosuppressive therapy can put transplant patients at risk of late acute graft rejection. Improving adherence is essential to increasing patients’ graft survival.”

It is not only difficult to quantify the percentage of graft loss actually due to non-adherence in the post-transplant population, it is even more problematic to identify patients at increased risk of non-adherence, according to Dr. Arthur Matas, Director, Renal Transplant Service, University of Minnesota, Minneapolis. Nevertheless, a study by Dew et al. (Liver Transpl 2006;12:1736-40) reported that 22% of transplant patients were non-adherent to immunosuppressive medication and kidney transplant recipients were at the highest risk.

Comparable Results

Dr. Bernhard Krämer, Director, Nephrology and Renal Transplantation, University Hospital of Regensburg, Germany, noted that findings from pharmacokinetic studies, phase II clinical trials and a phase III trial clearly demonstrated that prolonged-release, once-daily tacrolimus is therapeutically equivalent to the standard twice-daily formulation with regard to AUC0-24 in de novo renal transplant recipients.

“Furthermore,” he remarked, “tacrolimus trough levels with both formulations are highly correlated with AUC0-24, suggesting that whole-blood tacrolimus trough levels can easily be used as a surrogate marker for AUC0-24 with the new once-daily tacrolimus formulation.”

In the phase III trial, which compared the two tacrolimus formulations to cyclosporin (CsA) microemulsion, Dr. Krämer reported that 638 adult de novo kidney transplant patients were randomized to the once-daily prolonged-release formulation (0.15 to 0.20 mg/kg/day), twice-daily tacrolimus (0.075 to 0.10 mg/kg) or CsA (4 to 5 mg/kg) in two equal doses. All patients were given standard basiliximab induction, mycophenolate mofetil (MMF) and corticosteroid therapy. The primary end point was efficacy failure rate at one year.

“The post-transplant efficacy failure rate at one year was comparable between the prolonged-release tacrolimus formulation [14%)], the standard twice-daily formulation [15.1%] and CsA treatment groups [17.0%],” he reported (Figure 1). “On the other hand, the 14% rate of biopsy-proven acute rejection was higher with CsA at one year than with either once-daily or standard tacrolimus at 10% and 7.5%, respectively, which was a statistically significant [P£0.04] superiority of the conventional tacrolimus formulation over CsA (Figure 2). One-year patient and graft survival rates were 98.6% and 96.7%, 95.7% and 92.9%, and 97.6% and 95.7%, respectively, for prolonged-release, standard-formulation tacrolimus and CsA, respectively.”

Figure 1. Post-transplant Failure Rate at One Year

He noted, too, that the safety profile of the prolonged-release formulation is comparable to the established safety profile of the twice-daily formulation. “With regard to renal function at two years, serum creatinine or estimated glomerular filtration rate was excellent and very similar between groups.”

Dr. Krämer explained phase II conversion studies have demonstrated that stable renal transplant recipients can conveniently be switched from the twice-daily to the prolonged-release formulation to take advantage of the more simplified dosing interval. Conversion is based on a milligram-for-milligram daily dose conversion, and although dose adjustments may be made following conversion to maintain trough concentrations, 70% of kidney patients have not required any dose adjustments during pharmacokinetic evaluations. Additionally, there is a strong correlation between systemic exposure (AUC0-24) and trough levels (Cmin) for both formulations, allowing blood monitoring systems already in place for the twice-daily dosing to be used for the once-daily prolonged-release dosing.

Figure 2.
ejection at One Year

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Findings at Two Years

Prof. Zbigniew Wlodarczyk, Head, Transplant Surgery, Nicolaus Copernicus University, Torúns, Poland, followed 41 de novo kidney transplant recipients for two full years beyond a randomized, comparative six-week study of pharmacokinetic profiling. Patients were given an initial daily prolonged-release tacrolimus dose of 0.15 mg/kg. Prof. Wlodarczyk reported no deaths or graft losses during the extended period of immunosuppression with tacrolimus, so patient survival was 100%. Four acute rejection episodes were recorded, three of which were biopsy-proven, and all responded to corticosteroid therapy. Creatinine clearance remained stable throughout follow-up.

Dr. Ploeg concluded that improving adherence is essential to increasing patient and graft survival. Patients who are fortunate enough to receive an organ should be helped with the most convenient post-transplant regimen available in order to maintain compliance and adherence.