Prediction of the disposition of beta-lactam antibiotics in humans from pharmacokinetic parameters in animals

Abstract

Various pharmacokinetic parameters (disposition half-life, total body clearance, renal clearance, hepatic clearance, volume of distribution, intrinsic clearance and volume of distribution of unbound drug) of six beta-lactam antibiotics were compared in mouse, rat, rabbit, dog, monkey, and human. Two methods for prediction of the disposition of the beta-lactam antibiotics in humans by extrapolation of the animal data were evaluated. One was the Adolph-Dedrick approach, which can be used to predict clearances in humans from the relationship between intrinsic clearances and body weight in the other five species. The volume of distribution in humans was predicted from the relationship between the volume of distribution and serum unbound fraction in the five species. The other was the Boxenbaum approach, which can be used to predict the pharmacokinetic parameters of the six beta-lactam antibiotics in humans by using the regression lines of log-log plots of intrinsic clearance and volume of distribution of unbound drug in a single species, in this case the monkey. The half-life calculated according to the latter method had a smaller absolute error than that calculated according to the former method, but the better method for extrapolation of animal data to humans seems to be the former method, which does not require a priori information regarding structure-pharmacokinetic relationships among the antibiotics.