Interspecies pharmacokinetic scaling of a new carbapenem, DA-1131, in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics.
The total body clearance (CI), renal clearance (CIr), 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[CI (L h-1)] and log[W (kg)] (r = 0.995; p = 0.00503), log [CI, (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 CI = 0.706W 0811, CIr = 0.318W 0.888, an V88 = 0.194W 0981. These allometric equations were extrapolated to predict the CI and Vss for DA-1131 in humans based on 70 kg body weight. The CI 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 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.
Kim
S H
SH
College of Pharmacy, Seoul National University, Republic of Korea.
Kim
W B
WB
Lee
M G
MG
D000818:Animals; D015780:Carbapenems / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011237:Predictive Value of Tests; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution
D015780:Carbapenems; C099230:DA 1131