Safety, tolerability and pharmacokinetics of higher‐dose mizoribine in healthy male volunteers
D Stypinski, M Obaidi, M Combs… - British journal of …, 2007 - Wiley Online Library
D Stypinski, M Obaidi, M Combs, M Weber, AJ Stewart, H Ishikawa
British journal of clinical pharmacology, 2007•Wiley Online LibraryAims 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≥ 0.5 but< 3 µg 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 …
prevention of rejection in renal transplantation. Its therapeutic window is based on trough
concentrations staying at≥ 0.5 but< 3 µg 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 …
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 ≥0.5 but <3 µg 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.
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