May 2001

From University of Michigan Health System

Newer form of 'gold standard' drug helps kidney transplant patients do better in long term

Kidney transplant patients fare better over the long term with newer form of "gold standard" drug, study finds

ANN ARBOR, MI - A reformulation of the "gold standard" drug against kidney transplant rejection not only costs less and gets absorbed better - it also helps transplant recipients keep their new organs longer.

That's the finding of a new University of Michigan Health System study that answers a question pondered by transplant physicians and tens of thousands of transplant patients for nearly six years: was there any long-term advantage to using one form of cyclosporine or the other?

The new data suggest there was indeed. Patients who took the microemulsion form of the drug, introduced in 1995, had a significantly lower risk of suffering chronic failure of their transplanted kidney than those who used the older form of the same drug. The results, from one of the largest studies of its kind, will be presented May 14 in Chicago at Transplant 2001, the annual meeting of the American Society of Transplantation.

"As the pharmaceutical industry continues to introduce new forms of established medications, we who care for patients must constantly ask the question, 'Is this really an improvement overall?'," says Bruce Kaplan, M.D., co-author of the study and associate professor of nephrology in the U-M Medical School and co-medical director of renal transplantation at UMHS. "In the case of cyclosporine, it appears the answer is yes all around."

The study looked back at the experiences of 29,786 people who received kidney transplants between 1994 and 1997, and whose medical histories were recorded anonymously by the United States Renal Data System.

Kaplan worked with co-author Herwig-Ulf Meier-Kriesche, M.D., an assistant professor of nephrology at UMMS, to sort out which had been treated with the older and newer forms of cyclosporine, and how they fared during the first four years after their transplant.

Since the new form of cyclosporine has already been shown to reduce acute rejection, the researchers were most interested in the issue of long term kidney, or allograft, survival; patients who lost their new kidneys within 6 months of transplant were excluded. Differences in patient gender, race, use of other medications and other factors were corrected for.

In all, 92.4 percent of those who used the newer form of cyclosporine still had their new kidneys four years after their transplant, compared with 86.7 percent of those who took the older form. Those taking the newer drug had a 0.60 relative risk of chronic transplant failure when compared taking the older form.

Cyclosporine, derived from fungus and used for nearly two decades as the "gold standard" drug to prevent transplant recipients from rejecting their new organs and tissues, is the most widely used transplant drug in the world.

The effectiveness of the drug - and its tendency to cause side effects - varies with the amount that reaches the patient's bloodstream after being swallowed. The original form of cyclosporine was absorbed differently by different patients depending on their body's ability to produce digestive juices or even what they ate.

So, the newer formulation introduced in 1995 under the name Neoral was looked upon as an improvement because its microemulsion form made cyclosporine available in the body more consistently and in more patients. The lower cost of the new form was seen as an added benefit.

As a result, most transplant programs, including the U-M's, switched to the new form in the mid-1990s, making it part of the post-transplant regimen of nearly all organ recipients. More than 13,000 people receive a new kidney or kidney and pancreas each year.

A similar drug, tacrolimus, or FK506, also became available to patients during the same time period. Since then, generic versions of reformulated cyclosporine have come on the market. Meanwhile, another medication, mycophenolate mofetil, or MMF, has reached widespread use as an anti-rejection drug to be taken along with cyclosporine.

Kaplan and Meier-Kriesche embarked on the new study to assess the longterm effect of the trend toward using the newer drugs. They used the USRDS, which until 1999 was based at UMHS, and which collects, analyzes and distributes data on end-stage renal disease and provides a basis for research like the new U-M study.

The study's results, Kaplan and Meier-Kriesche say, offer "strong advocacy" for the use of the newer form of cyclosporine over the old for aiding long-term allograft survival, whether or not MMF is also taken.

"This reaffirms the important role of the calcineurin inhibitors, such as cyclosporine and tacrolimus, for long-term survival of a transplanted kidney," Kaplan concludes. "This is important because nearly all transplant recipients in the U.S. rely on these drugs to improve their chances of maintaining their new organs."

Disclosure: Although this study was not funded by Novartis, the manufacturer of Neoral, Dr. Kaplan received funding for other studies of anti-rejection medications from the company.












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