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Prediction of the Disposition of Midazolam in Surgical Patients by a Physiologically Based Pharmacokinetic Model by Sven Björkman; D. Russell Wada; Britt-Marie Berling; Göran Benoni is a Chemistry article available to read on EtoBox.

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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 coef®cients (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 ̄ow. Curves of midazolam plasma concentration versus time were ®nally predicted by means of a perfusion-limited PBPK model and compared with measured data. In a ®rst study on 14 young patients undergoing surgery with modest blood loss, V dss was predicted with an only 3.4% mean error (range À24±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 s

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Author

Sven Björkman; D. Russell Wada; Britt-Marie Berling; Göran Benoni

Publisher

John Wiley and Sons; Elsevier ; Elsevier Inc.; Elsevier BV (ISSN 0022-3549)

Published

2001

Language

EN

Field

Chemistry (Physical Sciences)