Safety, tolerability and pharmacokinetics of higher-dose mizoribine in healthy male volunteers.

AIMS: Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at > or =0.5 but <3 microg ml(-1). It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2-5 mg kg(-1) day(-1). The safety, tolerability and pharmacokinetics from two clinical trials of higher-dose mizoribine treatments in healthy male volunteers are presented. METHODS: Forty-eight healthy White male nonsmokers participated in two randomized, double-blind, placebo-controlled trials: 32 in a single-dose study (3, 6, 9 and 12 mg kg(-1)) and 16 in a multiple-dose study [6 mg kg(-1) day(-1) once daily for 5 days or twice daily (12 mg kg(-1) day(-1)) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed. RESULTS: The safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg(-1) day(-1)) in the multiple-dose study. Orally administered mizoribine reached peak concentrations within 2-3 h and was eliminated mostly via the kidney (65-100% of dose) with a 3-h half-life. Only the 12 mg kg(-1) day(-1) group achieved trough concentrations that were within the therapeutic window. Conclusions Based on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6-12 mg kg(-1) day(-1) range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.