1996 Volume 27 Issue 4 Pages 759-769
In the development of new drugs, administration doses in a clinical phase I study and the expected final clinical dose were determined from the pharmacological data and nontoxic dose in repeated toxicity studies in an animal experiment. In this report, we comparatively examined the pharmacokinetic and toxicokinetic parameters in experimental animal studies and data from human clinical treatment of drugs under clinical development. Normalized AUC of rats, dogs and humans were calculated on the basis of 1mg/kg dose. The AUC ratios between rats, dogs and humans were widely distributed as one peak modality. The median of AUC ratio (human/rat) was 7.0 and that of AUC ratio (human/dog) was 2.89. However, the AUC ratios under 1.0 were found to be 12% and 20%, respectively, in human/rat and human/dog. The AUC obtained in the nontoxic dose of rats and dogs were compared with that obtained in the clinical (single) dose. The medians of the AUC ratios were 4.64 and 6.29, respectively, in rat/human and dog/human. However, the AUC ratios of under 1.0 were found to be 24% and 13%, respectively, in rat/human and dog/human. Normalized peak concentrations in plasma of rats, dogs and humans were calculated on the basis of 1mg/kg dose. The peak concentration ratios between rats, dogs and humans were widely distributed as one peak modality. The median of the peak concentration ratio in human/rat was 3.53 and that of human/dog was 1.96. However, the peak concentration ratios under 1.0 were found to be 18% and 32%, respectively, in human/rat and human/dog. The peak concentration obtained in nontoxic doses of rat and dog were compared with that obtained in the clinical dose. The medians of the peak concentration ratios were 2.21 and 5.19, respectively, in rat/human and dog/human. However, the peak concentrations under 1.0 were found to be 23% and 12%, respectively, in rat/human and dog/human. These results clearly revealed the presence of numerous drugs which showed lower exposure levels of dosed drugs in the nontoxic dose administration than in the clinical dose administration. These results might indicate that the safety of these drugs was not guaranteed from the viewpoint of toxicokinetics. However, these results rather might be due to following reasons that the metabolic rate in rats is faster than humans and the toxicity of metabolites may lower the nontoxic dose. Therefore, pharmacokinetic studies on toxic metabolites will be required and the evaluation of the contribution of metabolites in drug toxicity will be essential in future toxicokinetic studies.
