ILTS 2016 Report: Once-daily tacrolimus sees favourable results worldwide

by Thomas R. Collins: Leading transplant experts say they’ve had a good experience using the once-a-day tacrolimus regimen, reporting better patient adherence compared to the twice-a-day version, along with as-good, or better, graft and patient survival.

At King’s College London, researchers studied results from 129 patients, 64 of whom received once-daily tacrolimus (Advagraf) early in their treatment course, or within a month after transplantation, and 65 who were converted from the twice-daily regimen more than a month, averaging about a year, after transplant. These were compared to results from 60 controls receiving twice-daily tacrolimus without ever converting.

Patients who were converted were switched at the discretion of a doctor, often for a high rate of acute cellular rejection. Once converted, these patients — who were much younger in age than those who did not convert — saw their rejection rate drop to 11%, far lower than the 50% rejection seen before the switch.

“That was a significant change,” said Dr Varuna Aluvihare, Consultant Hepatologist at King’s.

Researchers also found lower variability in tacrolimus concentrations among those taking the once-a-day medication, and reduced variability in concentrations for those who switched.

“This is a good surrogate marker for improved adherence,” Dr. Aluvihare said.

A larger study, including about 500 on once-daily tacrolimus and 3,800 on twice-daily tacrolimus, found a rate of graft survival that was 8% better in the once-a-day group compared to the twice-a-day group, and patient survival that was 7% better.

“That would mean for every 13 patients treated with once daily tacrolimus there would be one life saved,” he said. “And that is a significant change.”

He cautioned that this was registry data and might not be free from selection bias, that there was a lack of information about levels of the drug and a lack of discussion about mechanism, and no validation cohort.

But, he said, “I think this certainly raises the question of whether patients will be better off on once-daily tacrolimus.”

New data suggest that, for best results in renal function, tacrolimus use needs to be tailored to the patient.

Professor Giuseppe Tisone, Director of the Transplant Centre at the University of Rome, presented a new analysis of data from the DIAMOND trial, which compared early once-daily tacrolimus dosing plus mycophenolate mofetil to reduced dosing plus MMF and basiliximab to delayed use plus MMF and basiliximab.

Researchers found, that, for those with a baseline eGFR of 60 or higher, initial lower dosing of the drug was associated with a renal function benefit compared to a higher dose or a delayed dose. For those with a baseline eGFR of 30 to 59, a renal function improvement from baseline to week 24 was seen with the lower dose or delayed use, while a renal function decline was seen with an initial higher dose. And for those with a baseline eGFR of less than 30, delaying use until Day 5 was associated with a significantly higher eGFR at week 24, compared to immediate dosing.

In India, at the Ang Centre for Liver and Biliary Surgery, patients on monotherapy with tacrolimus are offered the once-a-day regimen after one year.

Researchers looked at 60 patients pre- and post-conversion. Many switched mainly for convenience, others for reasons such as raised creatinine levels and for tremors. Researchers found improved creatinine levels after conversion.

“And there was marked improvement in diarrhoea,” said Subash Gupta, MD, director and founder of liver transplant and hepato-pancreato-biliary surgery at the centre. “So convenience and tolerability with the Advagraf was better in the long term. An unusual observation in our population was improvement in renal function, and may have been related to lower tacrolimus levels after conversion.”

At National Taiwan University Hospital, in a review of results from more than 400 transplants — in which 101 patients received once-daily tacrolimus from the time of transplant — survival was statistically the same for the once-daily regimen, compared to other immunosuppressive regimens.

Rey-Heng Hu, Professor of Surgery at the university, noted that the renal benefits were not seen in his cohort. But the results, given the convenience, are encouraging for the once-a-day option, he said.

“It is safe effective,” he said, “to use Advagraf from the beginning of (the) liver transplant.”

References

Considine A, Tredger JM, Heneghan M, et al. Performance of modified-release tacrolimus after conversion in liver transplant patients indicates potentially favorable outcomes in selected cohorts. Liver Transpl. 2015 Jan;21(1):29-37.

Adam R, Karam V, Delvart V, et al. Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European Liver Transplant Registry. Am J Transplant. 2015 May;15(5):1267-82.