Prediction of lidocaine tissue concentrations following different dose regimes during cardiac arrest using a physiologically based pharmacokinetic model

Background: The purpose of our study was to develop a physiologically based pharmacokinetic (PBPK) model describing the behavior of lidocaine in human s by scaling up physiological variables from animal models of cardiac arres t. We attempted to identify the optimal dose regime for lidocaine during ca rdiac arrest using this model. Methods and results: We designed a flow-depe ndent PBPK model representing nine body tissues for lidocaine. Physiologica l organ flow rates, tissue volumes, and plasma-tissue partition parameters for lidocaine in humans were taken from the literature. Data from published animal studies were used to estimate loss of organ blood flow during cardi ac arrest and lidocaine tissue partition coefficients. The model assumed a 70 kg cardiac arrest patient. The following five lidocaine dose regimes wer e simulated: (1) 4 mg/kg IV push (IVP) (2) 1.5 mg/kg IVP then 1.5 mg/kg IVP in 4 min., (3) 3 mg/kg IVP, (4) 2 mg/kg IVP, and (5) 1.5 mg/kg IVP. A simu lation of Regimen 2, which is the current American Heart Association (AHA) recommendation, suggests that the concentration of lidocaine is suboptimal at the decision point (3-5 min) to administer another dose. Regimen 4 offer s a slightly more rapid progress towards optimal cardiac concentrations and more acceptable brain concentrations compared to regimes 1-3. Conclusion: Simulations from our PBPK model suggest that the current AHA lidocaine dose regime for cardiac arrest may not result in optimal lidocaine concentratio ns in the heart and brain. Simulations suggest that 2 mg/kg IVP may be the most acceptable lidocaine dose regime during cardiac arrest. (C) 2001 Elsev ier Science Ireland Ltd. All rights reserved.