Prediction of the disposition ofβ-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.

Allometric scaling of xenobiotic clearance: Uncertainty versus universality

“…The major interest has been prediction of pharmacokinetic parameters in man from parameter values determined in animals [10][11][12][13][14][15] . Clearance has been the most studied parameter, as it determines the drug-dosing rate.…”

COMPARISON OF PREDICTION METHODS FOR IN VIVO CLEARANCE OF (S,S)-3-[3-(METHYLSULFONYL)PHENYL]-1-PROPYLPIPERIDINE HYDROCHLORIDE, A DOPAMINE D2 RECEPTOR ANTAGONIST, IN HUMANS

“…Considerations of the relationship between drug elimination and physiological parameters such as hepatic or renal blood flow reasonably led to the application of allometric scaling in correlating pharmacokinetics in humans and animal species (Boxenbaum, 1980;Ings, 1990;Ritschel, 1992). Accurate predictions of pharmacokinetics in human by allometric scaling were demonstrated for renally excreted antibiotics (Sawada et al, 1984;Mordenti, 1986) and proteins (Mordenti et al, 1991) as well as for a number of drugs displaying high hepatic extraction (Boxenbaum and D'Souza, 1990). However, for compounds characterized by low and intermediate hepatic extraction, elimination strongly depends on biochemical parameters such as intrinsic clearance and protein binding, which often are highly species specific.…”

Issues Related to the Use of Canines in Toxicologic Pathology—Issues With Pharmacokinetics and Metabolism

“…Despite the complex interplay of the components of the renal excretory process, several investigators have been successful in performing allometric scaling using the renal excretion parameters of several species, including dogs. In these cases, the renal excretion parameters in the dog correlated well with those of other species (24,32,55,64). However, caution is advised even when studying the renal excretion within a single class of molecules.…”