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.

PRIORITY PRESS - 17th Congress of the International Liver Transplantation Society (ILTS)

Valencia, Spain / June 22-25, 2011

Chief Medical Editor: Dr. Julie Frère, Montréal, Quebec

Agents with a comparatively narrow therapeutic window, such as calcineurin inhibitors (CNIs), often perform better when offered in extended-release formulations, as release of the active moiety in the gastrointestinal (GI) tract can be controlled and peaks in absorption avoided. With controlled absorption, it is also easier to maintain steady plasma concentrations and reduce the risk of toxicity. Extended-release formulations typically allow for q.d. dosing, a feature that can promote better adherence regardless of the condition for which a drug is indicated.

Several studies were presented at the ILTS comparing the safety and efficacy of b.i.d. tacrolimus to its q.d., extended-release formulation in liver transplant recipients. In a comparative study, researchers from 4 transplant centres in Taiwan randomized 48 de novo liver transplant recipients to receive tacrolimus, once or twice a day, for 12 months. The initial dosing ratio was 1:1. The primary end point was the rate of biopsy-proven acute rejection (BPAR) at 6 months.

As reported by Tan et al. (Poster P-453), the incidence of BPAR at 6 months was 4.5% for the extended-release formulation vs. 13% for the conventional b.i.d. group. At 12 months, BPAR rates were 9.1% for the q.d. group vs. 17.4% for the b.i.d. group. The average time to the occurrence of BPAR was shorter for the q.d. group at 68 days compared to 117 days for the b.i.d. group, although this difference was not significant (P=0.655). However, the severity of the BPAR episodes, as reflected by the Banff Rejection Activity Index score, was comparable in both groups, and mean trough levels were also comparable in both groups. Despite a higher incidence of pre-existing hypertension (P=0.01) and diabetes (P=0.135) in the q.d. group, increases in blood pressure and fasting blood glucose levels at 12 months were not statistically different between the 2 groups and trends in hepatic, renal and lipid profiles were also equivalent.

At 12 months, patient and graft survival rates were excellent, at 86.3% in the q.d. group vs. 95.6% in the b.i.d. group (P=0.263).

In another de novo liver transplant population (n=100), the efficacy, trough levels and doses of the extended-release formulation were again compared to the conventional b.i.d. formulation. All but a minority of patients initially received the extended-release formulation plus either steroids, mycophenolate mofetil (MMF) or MMF plus steroids.

As reported by Ortiz de Urbina et al. (Poster P-66), patient and graft survival were both 100% at 6 months in the q.d. formulation group vs. 98% and 96%, respectively, for patients receiving the conventional formulation. On day 2, trough levels of extended-release tacrolimus were 9.4 ng/mL vs. 12.3 ng/mL for the conventional formulation. At day 180, trough levels were again similar at 8.1 ng/mL and 7.0 ng/mL in the once vs. twice-daily groups, respectively. Two patients did discontinue the extended release formulation during the study but overall, both formulations were effective and well-tolerated, as concluded by the authors.

Del Gaudio et al. (Poster P-257) analyzed outcomes in 200 stable liver transplant recipients who were converted from b.i.d. to q.d. tacrolimus. Before switching, trough levels of the conventional formulation were 4.9 ng/mL.

After the switch, trough levels were 4.05 ng/mL, 4.5 ng/mL and 4.05 ng/mL at 10 days, 3 months and 6 months, respectively. The majority of patients did not require any change in dosing following the conversion and changes in creatinine, bilirubin and liver enzymes pre- and post-switching were also minimal. There were no episodes of acute rejection following the switch.

Results from this study suggest that stable liver transplant recipients receiving conventional tacrolimus can be safely switched to the q.d. extended-release formulation with minimal dose adjustments.

The Role of mTOR Inhibitors in Transplantation

The mTOR inhibitors are similarly indicated in a number of transplant settings, including liver transplantation. As reported by Bilbao et al. (Poster P-68), investigators described findings in 62 liver transplant recipients at Hospital Vall d’Hebron, Barcelona, Spain, who were treated with everolimus. Between October 1988 and July 2010, the centre performed 928 liver transplantations; 62 patients (6.7% overall) received everolimus. At the time of conversion from their original immunosuppressive regimen to everolimus, approximately one-quarter of recipients had evidence of refractory rejection.

As investigators reported, the mean time from liver transplantation to mTOR inhibitor conversion was 26 months (median 6 months). At the time of conversion, 16 patients had renal insufficiency, 18 had arterial hypertension, 18 had diabetes and 26 had hyperlipidemia.

Everolimus was combined with tacrolimus in 43 patients, with cyclosporine in 3 patients, with MMF (with or without steroids) in 9 and with steroids in 5. Trough levels of everolimus were 3 ng/mL. Out of the 62 patients, conversion to everolimus resolved the cause of conversion in 64%. Importantly as well, approximately half of those with renal insufficiency and diabetes reverted to their baseline state. Hyperlipidemia occurred in 45% of those who were converted to the mTOR inhibitor and 9 patients withdrew from everolimus due to either lack of efficacy or to adverse events (AEs).

Hepatitis C Infection

As noted by Charlton et al. (Liver Transpl 2004;10:1120-30), hepatitis C (HCV) infection remains the most common indication for liver transplantation and post-transplant recurrence of HCV is the most common cause of graft failure and death in these patients.

A recent analysis of prospectively gathered data from the United Network for Organ Sharing registry shows that patients who receive cyclosporine following liver transplantation due to HCV are at increased risk of BPAR, graft failure and death compared to those who receive tacrolimus (Irish et al. Am J Transplant 2011 [epub ahead of print]). In a study presented at the ILTS by Lladó et al. (Poster P-64), investigators compared the incidence and severity of HCV recurrence following liver transplantation according to CNI immunosuppressant received.

The study took place between March 2007 and April 2010, with 27 patients receiving a cyclosporine-based regimen from day 1 (10 mg/day) and 23 receiving a regimen containing tacrolimus (0.1 mg/kg/day), again from day 1. Both groups received basiliximab on day 0 and 4 and MMF 2 g/day if creatinine levels >125 µmol/L. Neither group received steroids. Protocol biopsies were carried out at 6 months and yearly after that.

The incidence of rejection was higher at 24% (6 patients) in the group that received the cyclosporine-based regimen compared with 0% for those who received the tacrolimus-based regimen (P=0.008). At 12 months, the rate of fibrosis was also numerically higher in the cyclosporine-based group, as was the proportion of patients requiring antiviral treatment. The differences between the 2 groups on both of these end points were not, however, statistically significant. In contrast, there was no difference in overall survival or AEs between the 2 groups.

Summary

As in most other therapeutic areas, adherence remains an issue in transplant recipients. Simplifying the immunosuppressive regimen is one way in which to bolster adherence and a q.d. extended-release formulation represents a more convenient strategy than conventional dosing. With a number of studies now having demonstrated that an extended-release formulation of the CNI tacrolimus provides equivalent immunosuppression and a safety profile similar to the conventional formulation, physicians now have an alternative option to offer transplant recipients in the hopes that q.d. dosing will translate into improved adherence and more robust outcomes in patient and graft survival.