Prediction of human pharmacokinetics of panipenem-betamipron, a new carbapenem, from animal data

Abstract

The pharmacokinetic behavior of panipenem (PAPM)-betamipron (BP), a new carbapenem, in humans was successfully predicted from data collected from six animal species. PAPM and BP were biphasically eliminated from plasma after intravenous (i.v.) administration of PAPM-BP to mice, guinea pigs, rats, rabbits, monkeys, and dogs. Elimination rates of PAPM and BP were correlated with animal size: the larger the animal was, the slower the elimination was. As for PAPM and BP, log-log plots of total plasma clearance (CLtot) versus body weight and log-log plots of distribution volume at steady state (VSS) versus body weight for six animal species were linear, with high correlation coefficients. These allometric equations were extrapolated to predict CLtot and VSS for PAPM and BP in humans. In addition, concentration in plasma-time profiles for humans were predicted by using two-exponent equations fitted to the complex Dedrick plot of animal data. Predicted values for CLtot and VSS for PAPM and BP in humans agreed well with observed values in humans given 750/750 mg of PAPM-BP as an i.v. drip infusion for 30 min. Predicted concentration in plasma-time profiles for humans approximated observed profiles. Thus, the pharmacokinetics of PAPM-BP extrapolated well from animal species to humans when allometric equations and the complex Dedrick plot were used.