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.

26th Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation

Madrid, Spain / April 5-8, 2006

The International Society for Heart and Lung Transplantation registry shows that use of the calcineurin inhibitor (CI) tacrolimus in heart transplantation has increased from less than 10% in 1999 to 46% in 2003 compared with cyclosporine, which was used in 89% of patients in 1999 and 48% in 2003. According to Dr. David O. Taylor, Department of Cardiology, Cleveland Clinic Foundation, Ohio, “This change is based on evidence from a series of relatively small clinical trials, starting in the second half of the 1990s.” Taken together, these early studies suggested that rejection and survival were similar for cyclosporine-based and tacrolimus-based regimens. Tacrolimus use was associated with less hypertension and less hyperlipidemia but also with more new-onset diabetes.

Recently, two large prospective, open-label, randomized clinical trials were conducted—one in the US and one in Europe—and their findings have prompted the use of tacrolimus as a first-line therapy in heart transplantation. In the US trial, 343 heart transplant recipients were randomized to receive corticosteroids and tacrolimus/sirolimus, tacrolimus/mycophenolate mofetil (MMF) or cyclosporine/MMF for one year (Kobashigawa et al. Am J Transplant 2005;5(Suppl 11):250). Dr. Taylor concluded, “When combined with MMF, tacrolimus is associated with less acute rejection, less hypertension and less hyperlipidemia than cyclosporine.” In combination with sirolimus, tacrolimus was highly efficacious, but like cyclosporine, associated with increased renal insufficiency. Moreover, optimal dosing has yet to be determined.

Dr. Mauro Rinaldi, Cardiothoracic Surgery Division, Azienda Sanitaria Ospedaliera Molinette San Giovanni Battista, University of Turin, Italy, discussed the European multicentre study of cyclosporine and tacrolimus, the findings from which will be published shortly in the American Journal of Transplantation. After induction therapy (corticosteroids followed by antithymocyte globulin or muromonab-CD3), 314 patients were randomized to either tacrolimus or cyclosporine in combination with azathioprine and corticosteroids.

The survival rate after 18 months was 92.9% for patients treated with tacrolimus and 89.8% for those who received cyclosporine. After six months, a significant difference in the rate of high-grade rejection was apparent between the two groups (72% of patients were free from biopsy-proven acute rejection grade ³3A in the tacrolimus group compared to 58% in the cyclosporine arm [P=0.013]). In the safety analysis, significantly fewer tacrolimus-treated patients suffered new-onset hypertension (65.6%) compared to cyclosporine (77.7%). Likewise, significantly fewer tacrolimus-treated patients developed hyperlipidemia (28.7% vs. 40.1%, respectively). New-onset diabetes mellitus was, however, reported significantly more often with tacrolimus (20.3%) than with cyclosporine (10.5%). However, as Dr. Rinaldi explained, “Patients who developed diabetes tended to be older, and there is some evidence that lower doses of steroids reduce the incidence of new-onset diabetes to an acceptable rate.”

The limitations of the study included use of azathioprine as adjunctive therapy because MMF, which is now more widely used, had not been available when the study was initiated. Dr. Rinaldi concluded that the adverse-effect profile depends on the overall immunosuppressive regimen and warned that regimens free of CIs do not necessarily reduce the number of adverse effects.

Towards Tailored Regimens

Clinical trials with CIs provide important evidence about preferred regimens in certain clinical situations, but as Dr. Patricia Uber, Department of Medicine, University of Maryland, Baltimore, pointed out, “Heart transplant outcomes vary greatly according to the characteristics of the recipient.” Children and African Americans seem particularly susceptible to pharmacokinetic differences and interacting medications, underlining the importance of an accurate picture of treatment exposure (Mehra et al. Transplantation 2002;74(11):1568-73). Measurement of treatment concentrations at two hours’ post-administration rather than trough concentrations has been shown to provide a better indication of exposure to cyclosporine.

The microemulsion formulation of cyclosporine has been shown to improve exposure kinetics of this agent. In studies comparing immediate-release tacrolimus with a modified-release formulation, AUCs were similar. No acute rejection, deaths or graft loss was reported for patients who switched to the modified-release formulation, which may provide more consistent exposure kinetics in children and African Americans.

Different routes of administration have also been explored in an effort to control the exposure pharmacokinetics. Maximum tacrolimus concentrations after sublingual administration to four heart transplant patients (two African Americans and two Caucasians) were slightly lower than Cmax after oral administration. With sublingual administration of tacrolimus, measures need to be taken to counteract its unpleasant taste. Dr. Uber did not think that the sublingual formulation would replace oral therapy, but she indicated that it could be a valid option in some situations. A study that compared inhaled cyclosporine with placebo in lung transplant recipients showed significantly greater survival free of bronchiolitis obliterans after three years but no significant difference in the frequency of histological acute rejection. Dr. Uber noted that caution is needed when interpreting the findings of this study because of group imbalances between the placebo arm and the active treatment arm.

Genetic Variation and Calcineurin Inhibitor Effect

Dr. Steven Webber, Director, Pediatric Heart and Heart-Lung Transplantation, Children’s Hospital of Pittsburgh, Pennsylvania, explained that ethnic and other demographic differences might only partially explain the wide variety of outcomes with CI use in solid organ transplantation. For a full understanding of individual response to CIs, genetic variation would have to be taken into account. Ultimately, he stated, such an approach could help avoid systematic oversuppression and reduce side effects while maintaining optimal efficacy.

There are a number of candidate systems and pathways for study in pharmacogenomics, including cytokines/chemokines and their receptors, adhesion and costimulatory molecules. According to Dr. Webber, “There are an estimated 10 to 20 million genetic polymorphisms which occur in more than 5% of the general population, so biological considerations should be applied to narrow the search.” Genes such as ABCB1 (MDR1; encoding P-glycoprotein) and the CYP3A4/5 subfamily appear to play a role in determining CI exposure and efficacy and may largely explain racial variation in drug disposition. However, as Dr. Webber stressed, “These are highly complex biological systems, so it is extremely unlikely that a single polymorphism is going to have a profound effect.” Although this research is unlikely to have an immediate impact on clinical practice, genetic studies may one day be combined with traditional clinical considerations to improve outcomes with CIs.

Lung Transplantation

CIs also serve as highly efficacious immunosuppressive therapy in lung transplantation. In his review of studies on cyclosporine and tacrolimus, Dr. Walter Klepetko, Department of Cardiothoracic Surgery, Medical University of Vienna, Austria, concluded, “Current evidence for the superiority of either drug remains limited. When the results of an ongoing multicentre study become available next year, we will get more insight into which is better.” The findings of some studies, however, do suggest a tendency towards lower incidence of acute rejection with tacrolimus, which may lead to a lower rate of bronchiolitis obliterans.

Summary

“We have brought together new data in larger numbers of patients from a number of countries around the world and these efforts should continue,” Dr. Lori West, Professor of Pediatrics and Surgery, University of Alberta, told delegates. However, further research is needed regarding how individual genetic variability relates to clinical outcomes of transplantation. The biology is complex, but according to Dr. West, “We will be able to move towards tailored therapies to meet individual patient needs.”