Prograf plus rapamycin: combined use safe and effective

WASHINGTON, May 2 (PROTEXT/PRNewswire) - Prograf(r)(tacrolimus) can be used safely in combination with the new,adjunctive immunosuppressant, rapamycin, according to resultsannounced at the American Transplant Congress meeting hereyesterday. (1)

Antirejection therapy is usually based on the addition of oneor more adjunctive agents, such as steroids, mycophenolatemofetil or rapamycin, to a cornerstone immunosuppressant such asPrograf(r) or ciclosporin. When rapamycin was first launched,however, there were concerns that it might not be appropriate touse it in combination with Prograf(r) due to hypotheticalsimilarities in the mode of action of the two agents. Theseconcerns have since been dispelled, and clinical studies ofPrograf(r) and rapamycin in combination are now underway in manyfields of transplantation medicine.

The results of this study were announced by Dr ZbigniewWlodarczyk (Bydgoszcz, Poland). The 6-month study was conductedin adult kidney transplant patients, and was of a multinational,open-label, prospective design. In the first 3 months of thestudy, the safety of combining Prograf(r) and rapamycin, usingthree different doses of rapamycin to determine the best regimen,was examined. During the second three months, the equallyimportant question of whether rapamycin treatment can safelybe withdrawn was investigated.

A total of 104 kidney transplant patients took part in thestudy. A control group of 28 patients received therapy withPrograf(r) and steroids. In three other groups, Prograf(r) andsteroid treatment was maintained as in the control group, butonce-daily rapamycin was co-administered at a dose of either0.5mg (25 patients), 1mg (25 patients) or 2mg (26 patients). The results revealed a significantly reduced risk of acuterejection with the addition of rapamycin to Prograf(r). Thepercentage of rejection-free patients was 69.6% in the controlgroup receiving Prograf(r) and steroids, and 87.5%, 91.5% and95.8% with the addition of 0.5mg, 1mg and 2mg rapamycin,respectively (p=0.016). Although these data indicate thatrapamycin enhances the ability of Prograf(r) to prevent acuterejection early after renal transplantation, the number ofpatients free of more serious, steroid-resistant rejection wassimilar in all four groups - 92.6% among the control group, and87.5%, 95.8% and 95.8% with 0.5mg, 1mg and 2mg additionalrapamycin, respectively.

One particularly distinctive and important side effect ofrapamycin is that it increases cholesterol levels.(2) This may bea problem with long-term use, since transplant patients are atincreased risk of cardiovascular disease and this risk may beexacerbated by raised cholesterol.(3) This effect of rapamycin isdose-related, so it is important to select the minimum dose ofrapamycin that is clinically effective.

The tendency of rapamycin to increase cholesterol levels wasconfirmed by the results of the study.(1) In the group whoreceived no rapamycin, the incidence of hypercholesterolaemia(defined as total cholesterol of over 240mg/dL, or LDLcholesterol of over 160mg/dL) at 3 months after transplantationwas only 4.8%. By contrast, the incidence was 23.8% in patientsgiven rapamycin at a dose of 0.5mg, 30.0% in patients receiving1mg, and 52.4% in patients receiving the 2mg/day dose. There wereno other marked variations between the groups with regard tosafety or tolerability, with the exception of a trend towardsslight impairment of renal function in the rapamycin-treatedpatients.

Since rapamycin increases cholesterol levels, many physiciansmay only wish to use it in the first few months aftertransplantation when the risk of rejection is at its greatest. Itwas therefore important to demonstrate that rapamycin could bediscontinued at 3 months without significantly increasing therisk of rejection. The results of the second phase of thetrial confirmed that withdrawal of rapamycin was possible and didnot expose patients to an increased rejection risk. Moreover,withdrawing rapamycin led to an improvement in cholesterolprofile, and was also associated with improved renal function.

On the basis of these findings, Dr Wlodarczyk recommendedthat the 0.5mg dose of rapamycin is the most appropriate to usein combination with Prograf(r), since it is clinically effectivebut has the smallest effect on blood cholesterol levels. Theresults of this study also confirm that the withdrawal ofrapamycin when clinically appropriate can be carried out safely.

Fujisawa GmbH is a subsidiary of Fujisawa Pharmaceutical Co.,Ltd., based in Osaka, Japan. Fujisawa Pharmaceutical Co., Ltd. isamong the world's top 30 pharmaceutical companies and employsover 8000 people in Japan, Europe, North America and Asia. Sinceits launch of Prograf( in Japan in 1993, the first in the world,Fujisawa has become one of the world's leading transplant andimmunosuppression companies.

Fujisawa plans to maintain its commitment to transplantation,and is dedicated both to improving the results of solid-organtransplantation and to ensuring the health and quality of life ofpatients. Prograf( is currently available in nearly 50 countriesand forms the centrepiece of Fujisawa's continuing growth.Additional information on Fujisawa GmbH can be found on theCompany's Web site at http://www.fujisawaeurope.com. References1. Wlodarczyk Z, Squifflet J-P, van Hooff JP, Vanrenterghem Y,Paczek L. Tacrolimus in combination with rapamycin: results of amulticentre, randomised, dose-finding study. Presented at theAmerican Transplant Congress, Washington, USA, 26 April-1 May,2002. Abstract 1314.2. Groth CG, Backman L, Morales JM, and the Sirolimus RenalTransplant Group. Sirolimus (rapamycin)-based therapy in humanrenal transplantation: similar efficacy and different toxicitycompared with cyclosporine. Transplantation 1999;67:1036-42.3. Roodnat J, Mulder PGH, Zietse R, et al. Cholesterol as anindependent predictor of outcome after renal transplantation.Transplantation 2000;8:1704-10.Contact:Marité CruzFujisawa GmbH, Munich, GermanyT: +49 89 45442249F: +49 89 434129marite.cruz@fujisawa.de

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