Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model

The aim of this study was to predict the disposition of midazolam in individual surgical patients by physiologically based pharmacokinetic (PBPK) modeling and explore the causes of interindividual variability. Tissue-plasma partition coefficients (k(p)) were scaled from rat to human values by a physiologically realistic four-compartment model for each tissue, incorporating the measured unbound fraction (f(u)) of midazolam in the plasma of each patient. Body composition (lean body mass versus adipose tissue) was then estimated in each patient, and the volume of distribution at steady state (V-dss) of midazolam was calculated. Total clearance (CL) was calculated from unbound intrinsic CL, f(u), and estimated hepatic blood flow. Curves of midazolam plasma concentration versus time were finally predicted by means of a perfusion-limited PBPK model and compared with measured data. In a first study on 14 young patients undergoing surgery with modest blood loss, V-dss was predicted with an only 3.4% mean error (range -24-+39%) and a correlation between predicted and measured values of 0.818 (p < 0.001). Scaling of k(P) values by the four-compartment model gave better predictions of V-dss than scaling using unbound k(p). In the PBPK modeling, the mean standard deviation (SD) prediction error for all data was 9.7 +/- 33%. In a second study with 10 elderly patients undergoing orthopedic surgery, hemodilution and blood loss led to a higher fu of midazolam. The PBPK modeling correctly predicted a marked increase in V-dss, a smaller increase in CL, and a prolonged terminal half-life of midazolam, as compared with findings in the first study. Interindividual variation in the disposition of midazolam could thus in part be related to the physiological characteristics of the patients and the fu of the drug in their plasma. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.