THE SIDE-EFFECT PROFILE OF SIROLIMUS - A PHASE-I STUDY IN QUIESCENT CYCLOSPORINE-PREDNISONE-TREATED RENAL-TRANSPLANT PATIENTS

A 14-day ascending dose course of sirolimus (rapamycin, RAPA) was admi nistered to quiescent renal transplant patients receiving a double-dru g cyclosporine (CsA)/corticosteroid regimen in a double-blinded random ized study. Oral sirolimus or placebo was delivered twice daily in div ided doses for 13 days and a final dose was administered on the mornin g of study day 14. In addition, patients in the sirolimus- and placebo -treated groups were compared with a demographically matched, concurre ntly treated control cohort of 30 patients who received the same conce ntration-controlled CsA/corticosteroid regimen. The study cohort was p artitioned into four sirolimus dose level groups: placebo (0 mg/m(2)/d ay, N = 10), low dose (1 to 3 mg/m(2)/day, N = 9), medium dose (5 to 6 mg/m(2)/day, N = 9), and high dose (7 to 13 mg/m(2)/day, N = 12). The primary side effect of sirolimus was a reversible decrease in platele t (PLT) and white blood cell (WBC) counts. Cholesterol values increase d statistically significantly in the sirolimus-treated patients when c ompared with those of the placebo patients, but not when compared with those of the control group patients. There were no statistically sign ificant differences in the steady-state average concentrations of CsA among sirolimus dose groups (including placebo). No differences were o bserved between the pre- and post-sirolimus treatment values of systol ic and diastolic blood pressure values, glomerular filtration rates (G FR), serum creatinine values (S-Cr), and serum glutamic oxaloacetic tr ansaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) or trigl yceride levels. Because the principal side effects of sirolimus are di stinct from the principal nephrotoxic properties of CsA, this drug com bination may display potent immunosuppression without exacerbated toxi city.