Tolerability profile of sodium mycophenolate (ERL080) and mycophenolate mofetil with and without cyclosporine (Neoral) in the rat

Mycophenolic acid sodium salt (ERL080) is currently in Phase III clinical t rials for the prophylaxis of kidney transplant rejection upon coadministrat ion with Neoral (cyclosporin A microemulsion). To assess the relative side effect profile of ERL080 and MMF as drug substances in Lewis rats, a rat st rain commonly used in transplantation experiments, a comparative 4-week tol erability study was performed. Escalating doses of ERL080 and MMF were admi nistered orally at 10-30 mg/kg/d (i.e., doses within or above the immunosup pressive range in rats), either in single compound treatment or in combinat ion with cyclosporine (CsA) at a daily oral dose of 7.5 mg/kg. The compound s were well tolerated as documented by body weight monitoring, hematologic parameters, and weight and histology of organs. Major abnormalities observe d were a dose-dependent reduction in thymus weight associated with immunosu ppression, in some cases villous atrophy in the jejunum, a reduction in whi te blood cell counts and lymphocyte counts (mean value in distinct treatmen t groups not exceeding 40-50%), a decrease in red blood cell counts and hem oglobin concentration (at maximum 25-30%), and an increase in platelet coun ts tin some groups up to doubling). At a given dose, these adverse effects were slightly more pronounced for MMF than for ERL080, and for groups under CsA coadministration compared to both compounds given alone. No significan t potentiation effect of CsA on the changes induced by ERL080 or MMF was ob served. Moreover, there were no new toxic entities evident upon CsA microem ulsion coadministration. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.