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New Immunosuppressant Class Not Without Serious Concerns

Cheryl A. Thompson

Recently presented research suggests that transplant clinicians who prescribe or monitor a fairly new type of immunosuppressant should pay as much attention to the adverse drug effects as to graft acceptance and patient survival, particularly with off-label use.

One of these new agents, available in Europe and in the final stages of the U.S. approval process, caused such undesirable adverse events in one group of transplant recipients that 61% of those assigned to the agent in a study had stopped taking the drug within two years.

This finding and the results of other studies of immunosuppressants were reported April 21–24 at the annual meeting of the International Society of Heart and Lung Transplantation, held in San Francisco, California.

Sirolimus, on the U.S. market since 2000, and everolimus, the subject of an "approvable" letter issued in October 2003 by FDA to Novartis AG, suppress the immune system by inhibiting the activation of a regulatory kinase known as the mammalian target of rapamycin, or mTOR. Decreased activation of mTOR curtails the proliferation of T cells that normally occurs in response to certain cytokines.

Rapamycin is another name for sirolimus and is the basis for the drugs brand name, Rapamune, by Wyeth.

The mainstay of immunosuppressants, cyclosporine, has been used in the United States since 1983 (see table). Its actions include inhibiting calcineurin, a phosphatase that influences sodium transport in the distal convoluted tubule of kidney nephrons.

FDA-Approved Labeling of Immunosuppressants
for Preventing Organ Rejection
  Organ Transplanted
Immunosuppressant Heart Kidney Liver Lung
Cyclosporine Yes Yes Yes No
Everolimus Pending Pending No No
Sirolimus No Yes No No
Tacrolimus No Yes Yes No

Tacrolimus, available since 1994, also is a calcineurin inhibitor but reportedly not as nephrotoxic as cyclosporine.

Sirolimus. Judson M. Hunt, medical director of the heart transplant program at Medical City Dallas Hospital in Texas, reported that changing the immunosuppressant from cyclosporine to sirolimus helped the renal function of patients but created new problems.

The serum creatinine concentration decreased significantly in long-term, stable heart transplant recipients whose level had not reached 2.5 mg/dL, he said. But 7 of the 83 patients who agreed to change their therapy then discontinued sirolimus, he said, because of an acne-like rash, dose-related stomatitis, diarrhea, increase in serum lipid levels, personal reasons, and an episode of transplant rejection, which responded to corticosteroid therapy.

"There was a significant learning curve in terms of the use of this agent," Hunt said, referring to the relatively new immunosuppressant.

Not the least of his problems were delays in obtaining patients' whole-blood sirolimus concentrations for use in therapeutic drug monitoring.

Current methods for measuring sirolimus concentrations involve high-performance liquid chromatography with ultraviolet-light or mass-spectrometric detection. An automated sirolimus blood test for use with automated immunoassay systems will not be available before late 2004, one company has stated.

Hunt's sirolimus protocol called for an initial loading dose of 5 mg twice on day 1 and then 2 mg daily, a weekly blood sample for determination of the drug's concentration, and dosage adjustments to achieve a trough concentration of 6–12 ng/mL. This range is lower than the one recommended in the product's labeling for kidney transplant recipients no longer receiving cyclosporine therapy.

German researchers who, like Hunt, sought a regimen free of calcineurin inhibitors so patients could recover lost renal function, found that the adverse effects from sirolimus therapy were mild but common.

For example, the team from Munich's LMU University Hospital reported, among the 35 heart transplant recipients who changed from cyclosporine therapy to sirolimus, acne developed in 64%—double to triple the rates described for kidney transplant recipients in the product's labeling. The new regimen started with a 6-mg dose of sirolimus, continued at 2 mg daily, and was adjusted to achieve a trough concentration of 8–14 ng/mL.

Thus far, according to the poster presentation, none of the German patients had discontinued sirolimus therapy.

The FDA-approved labeling for sirolimus does not state the discontinuation rate by kidney transplant recipients, the only patient group officially recognized for treatment with the drug.

Everolimus. The newer mTOR inhibitor, everolimus, seems headed for greater problems regarding discontinuation than has been reported with sirolimus.

Howard J. Eisen,1 lead author of a 2003 article on the one-year efficacy and safety of everolimus 0.75 or 1.5 mg twice daily in heart transplant recipients, reported at the meeting that the 3-mg/day regimen still had the higher discontinuation rate at the end of 24 months. In the first 12 months, 22% of the 211 patients assigned to the higher dosage had discontinued therapy because of adverse events, compared with 16% of the 209 patients in the lower-dosage group and 13% of the 214 patients assigned to azathioprine 1–3 mg/kg/day. Patients also received cyclosporine, corticosteroids, and a lipid-lowering agent.

According to Novartis, the approvable letter from FDA pertains to the use of everolimus, or Certican, in combination with cyclosporine in heart or kidney transplant recipients to prevent organ rejection. The Eisen-led study was partly funded by Novartis.

The lower dosage of everolimus "appeared to be safer" than the higher dosage, said Eisen, who is medical director of the Heart Failure and Transplant Center at Temple University in Philadelphia, Pennsylvania.

But renal impairment remains a concern with both dosages, he noted, particularly in the first year of treatment. At 24 months, everolimus users had a mean serum creatinine concentration of 2.0 mg/dL, regardless of the dosage, and a mean creatinine clearance of 55 mL/min (1.5 mg/day) or 51 mL/min (3 mg/day)—relatively unchanged from the values at 12 months. Azathioprine users had corresponding 24-month values of 1.7 mg/dL and 68 mL/min.

Eisen said patients' drug concentrations were measured "but there was no therapeutic drug monitoring," adding that the study was designed several years ago.

Gregory I. Snell, with the Lung Transplantation Service at Alfred Hospital in Melbourne, Australia, said the loss of the initially superior efficacy of everolimus 3 mg/day over azathioprine 1–3 mg/kg/day in an international study might have been related to the unexpectedly high rate of discontinuation over time.

By the 24-month point in the 36-month randomized, double-blind study of 213 stable lung transplant recipients, Snell said, 61% of those assigned to everolimus therapy had stopped taking the drug, whereas only 46% of azathioprine users had discontinued the therapy. Also, the everolimus group had a significantly higher frequency of serious adverse events, particularly bacterial and fungal infections, than the azathioprine group. All patients also received cyclosporine and corticosteroids.

What had been at 12 months a significant difference between the occurrence of the drugs' primary efficacy endpoint—graft loss, decline in lung function, loss to follow-up, or death—disappeared at 24 months, he reported.

A Novartis presentation to investment analysts in 2003 indicated that the 1.5-mg/day regimen, or 0.75 mg twice daily, was the preferred one.

  1. Eisen HJ, Tuzcu EM, Dorent R et al., for the RAD B253 Study Group. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003; 349:847-58.