title: Safety, tolerability and pharmacokinetics of higher-dose mizoribine in healthy male volunteers.
abstract: OBJECTIVE
  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.
authors.affiliation: MDS Pharma Services, Lincoln, NE 68502, USA. daria.stypinski@mdsinc.com
authors.forename: Daria
authors.initials: D
authors.lastname: Stypinski
authors.forename: Mohammad
authors.initials: M
authors.lastname: Obaidi
authors.forename: Michelle
authors.initials: M
authors.lastname: Combs
authors.forename: Meg
authors.initials: M
authors.lastname: Weber
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Stewart
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ishikawa
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007136:Immunoglobulins / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D012263:Ribonucleosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine