Interspecies pharmacokinetic scaling of a new carbapenem, DA-1131, in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

Abstract

The total body clearance (Cl), renal clearance (Clr), and apparent volume of distribution at steady state (Vss) of DA‐1131, a new carbapenem, after intravenous (iv) administration of the drug, 50 mg kg−1, to mice, rats, rabbits, and dogs were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict these parameters in humans. Significant linear relationships were obtained between log[Cl (L h−1)] and log[W (kg)] (r = 0.995; p = 0.00503), log[Clr (L h−1)] and log[W (kg)] (r = 0.998; p = 0.0429), and log[Vss (L)] and log[W (kg)] (r = 0.987; p = 0.0126). The corresponding allometric equations were Cl = 0.706W0.811, Clr = 0.318W0.888, and Vss = 0.194W0.981. These allometric equations were extrapolated to predict the Cl and Vss for DA‐1131 in humans based on 70 kg body weight. The Cl and Vss for humans predicted from the four animal data well fitted to regression lines of animal data. Interspecies scale‐up of plasma concentration–time data for the four species using a complex Dedrick plot resulted in similar profiles. In addition, the concentration in plasma–time profile predicted using the four animal data well fitted to a complex Dedrick plot of animal data. Our results indicate that the DA‐1131 data obtained from laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies. © 1998 John Wiley & Sons, Ltd.

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.…”

A Comprehensive Quantitative and Qualitative Evaluation of Extrapolation of Intravenous Pharmacokinetic Parameters From Rat, Dog, and Monkey to Humans. I. Clearance

“…In conducting such extrapolation, one frequently used measure of predictive quality or extrapolation success is the degree of interspecies agreement (i.e., the r 2 value of the allometric linear regression); the correlation coefficient has also been used as a justification to exclude certain species from an extrapolation set (Chung et al, 1985;Brazzell et al, 1990;Efthymiopoulos et al, 1991;Cherkofsky, 1995;Feng et al, 1998;Kim et al, 1998;Sukbuntherng et al, 2001). Although previous investigations have demonstrated this idea to be incorrect for specific compounds (Ward et al, 2002), the present study demonstrates that an improved mathematical correlation coefficient does not signify an improved ability of allometric scaling to correctly predict human clearance on a more global basis.…”

SB-242235, a selective inhibitor of p38 mitogen-activated protein kinase. II: In vitro and in vivo metabolism studies and pharmacokinetic extrapolation to man

“…To attempt to circumvent any scaling liabilities associated with this non-linearity, only preclinical pharmacokinetic data obtained at the lowest administered dose was used to develop the allometric scaling. This approach to minimizing the e ect of saturable elimination is similar to that previously used for compounds exhibiting non-linear pharmacokinetics, including triclopyr (Timchalk and Nolan 1997) and the carbapenem antibiotic DA-1131 (Kim et al 1998), and appeared to be successful in this instance.…”