Biol. Pharm. Bull. 29(12) 2460—2464 (2006)

agent, which has been on the market since 1984 in Japan for the prevention of rejection in renal transplantation. In contrast to other immunosuppressive agents (e.g., azathioprine), mizoribine has been shown in animal experiments to lack oncogenicity and has shown clinically a low incidence of severe adverse drug reactions (such as myelosuppression and hepatotoxicity), making it useful in long-term immunosuppressive therapy. After oral administration, mizoribine is absorbed rapidly from the gastro-intestinal tract and distributed into living cells according to a concentration gradient between the extracellular and intracellular environment. It is completely eliminated from blood circulation within 24 h, and is excreted in urine (85%), feces (9.7%), and bile ( 1%). As elimination rate of mizoribine is highly dependent on renal function, low-dose mizoribine (1 to 3 mg/kg/d) was administered to patients whose renal function did not return soon after transplantation. However, renal function returns much earlier following transplantation due to the concomitant use of calcineurin inhibitors. High-dose mizoribine (5 mg/kg/d) has been administered since 1998 to a number of patients, and has been shown to be safe and well tolerated in renal transplant patients at doses up to 5 mg/kg/d. In addition, Akiyama et al. reported that patients treated with 5 mg/kg/d of mizoribine showed about 20% fewer acute rejection episodes at 3 months post-transplantation than those with 5 mg/kg/d of mizoribine. Recently, phase 1 singleand multiple-dose studies have been carried out to confirm the safety, tolerability, and pharmacokinetics of higher-dose (up to 12 mg/kg/d) mizoribine. In the phase 1 study, no notable or clinically relevant abnormality was observed in the clinical laboratory values except for transient elevation in serum uric acid at the highest dose level (multiple dose of 12 mg/kg/d). In the present study, to evaluate the pharmacokinetic characteristics of mizoribine in subjects with normal renal function, we estimated the population pharmacokinetic parameters of mizoribine using a nonlinear mixed effects model (NONMEM) program. Pharmacokinetic data for population analysis were obtained in the previous phase 1 study, where 24 healthy Caucasian male subjects participated in a singledose (3, 6, 9, 12 mg/kg) study, and 12 subjects participated in a multiple-dose (6, 12 mg/kg/d) study. In addition, to assess linearity and constancy in the pharmacokinetics of mizoribine, the pharmacokinetic parameters in individual 36 subjects were obtained from the population estimates according to Bayes’ theorem using the NONMEM post-hoc option. We further evaluated the precision of Bayesian analysis in the sparse sampling protocol by using pharmacokinetic data obtained from 24 subjects in the single-dose study.