INTERSPECIES PHARMACOKINETIC SCALING OF A NEW CARBAPENEM, DA-1131, INMICE, RATS, RABBITS AND DOGS, AND PREDICTION OF HUMAN PHARMACOKINETICS

The total body clearance (Cl), renal clearance (Cl,), and apparent vol ume of distribution at steady state (V-ss) of DA-1131, a new carbapene m, 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 lin ear relationships were obtained between log[Cl (L h(-1))] and log[W (k g)] (r=0.995; p = 0.00503), log[Cl-r (L h(-1))] and log[W (kg)] (r = 0 .998; p = 0.0429), and log[V-ss (L)] and log[W (kg)] (r = 0.987; p = 0 .0126). The corresponding allometric equations were C1 = D.706W(0.811) , Cl-r = 0.318W(0.888) and V-ss = 0.19-1W(0.981) These allometric equa tions were extrapolated to predict the C1 and V-ss for DA-1131 in huma ns based on 70 kg body weight. The C1 and V-ss for humans predicted fr om 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 th e four animal data well fitted to a complex Dedrick plot of animal dat a. Our results indicate that the DA-1131 data obtained from laboratory animals could be utilized to generate preliminary estimates of the ph armacokinetic parameters in humans. These parameters can sen e as guid elines for better planning of clinical studies. (C) 1998 John Wiley & Sons, Ltd.