2014 年 40 巻 11 号 p. 643-651
The large variability of the bioavailability (F) of mizoribine accelerates the positive correlation between the apparent volume of distribution (V/F) and the oral clearance (CL/F). The aim of the present study was to assess whether the variable F of mizoribine in healthy adult men is one of the factors in the interindividual pharmacokinetic variability of the drug. The serum concentration data of mizoribine were analyzed by the nonlinear mixed effects model program with first-order (FO), first-order conditional estimation (FOCE), and Laplacian methods. The 1-compartment model with absorption lag time and first-order absorption fitted well with healthy adult data, and there was a significant positive correlation between V/F and CL/F. The performance of FO method analysis for adult data was deteriorated considerably by misspecification of the random effect, whereas the FOCE method was robust for model misspecification. On the other hand, the performance of FOCE method analysis for the data obtained from pediatric patients with renal diseases was inferior to that of quasi-gold-standard Laplacian method analysis, probably because of the flip-flop problems in the conditional (Bayesian) estimation step of the FOCE analysis. The present findings confirm that F of mizoribine is variable in the healthy adult population, and also suggest that conditional estimation (FOCE and Laplacian) methods should be utilized positively and carefully while considering their advantages and disadvantages.
