RAD in de novo renal transplantation: comparison of three doses on the incidence and severity of acute rejection.
BACKGROUND
The effects of three doses of RAD (40-O-[2-hydroxyethyl]-rapamycin), a novel macrolide with potent immunosuppressive and antiproliferative properties, on the incidence and severity of acute rejection episodes as well as its tolerability were evaluated in a dose-ranging study in de novo renal transplant recipients.


METHODS
In this double-blind, parallel group, multicenter study, recipients were randomized to receive 1 mg, 2 mg, or 4 mg/day of RAD in combination with Neoral (cyclosporine, USP MODIFIED) and corticosteroids. The incidence and severity of biopsy-proven acute rejection episodes, graft survival, patient survival, infection rates, laboratory measurements, and adverse events were compared across groups after 6 months of therapy.


RESULTS
Among the 103 recipients, patients receiving 1, 2, or 4 mg/day experienced a 32.4%, 14.7%, or 25.7% incidence of biopsy-proven acute rejection episodes within the first 6 months posttransplantation, respectively. Even though the study was not powered to demonstrate efficacy, the incidence of moderate and severe acute rejection episodes was found to be significantly lower among patients in the 2 mg and 4 mg/day groups than in the 1 mg/day group (P=0.002 and P=0.006, respectively). Overall graft and patient survival rates were excellent. RAD was generally well tolerated. Although blood lipid levels increased in all groups, changes were manageable with lipid-lowering agents and did not warrant discontinuation of study medication. The incidence of viral and fungal infections was low; however, it was higher among recipients treated with 4 mg/day.


CONCLUSIONS
In combination with Neoral and corticosteroids, RAD doses of 2 mg and 4 mg/day resulted in lower rates of acute rejection episodes and efficacy failure than the 1 mg/day dose and were significantly more effective in reducing the severity of rejection. Large-scale, controlled, follow-up studies are currently in progress to confirm these initial findings.
Kahan
B D
BD
Division of Immunology and Organ Transplantation, The University of Texas Medical School at Houston, 6431 Fannin St., Suite 6.240, Houston, TX 77030, USA. Barry.D.Kahan@uth.tmc.edu
Kaplan
B
B
Lorber
M I
MI
Winkler
M
M
Cambon
N
N
Boger
R S
RS
D000208:Acute Disease; D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology* / Q000503:physiopathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015994:Incidence; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus