A Physiological Model to Evaluate Drug Kinetics in Patients with Hemorrhagic Shock Followed by Fluid Resuscitation: Application to Amoxicillin-clavulanate

Purpose To build a physiologically based pharmacokinetic model describing drug kinetics in interstitial fluid in case of hemorrhagic shock, and to propose a simple method to determine the subset of influential parameters that may be estimated with the data at hand. Methods The model, which accounts for alterations of regional blood flows and body water distribution, was fitted to amoxicillin and clavulanate kinetic data, assessed in 12 trauma patients with hemorrhagic shock by comparison with 12 healthy volunteers. The predictions were the free concentrations of amoxicillin and clavulanate in 14 organs. Results In all tissues of trauma patients, the rate of distribution was lower, but the steady-state level was higher than those in healthy participants. Blood volume was reduced by 25% and blood flow in organs other than lung, brain, and heart were reduced by 18%. Compared with healthy subjects, the time that free amoxicillin concentration remained above 8 mg/L in the interstitial fluid of trauma patients was higher in blood and muscles, and lower in the tendon compartment. Conclusions The results and predictions were consistent with the knowledge in this field. The model may be useful to optimize clinical trial designs and drug dosing regimens.