Dosage regimen design for pharmaceutical studies conducted in animals.
The selection of dosage regimens for different animal species requires the establishment of pharmacokinetic equivalency between species. Pharmacokinetic equivalency can be defined in terms of the magnitude of exposure (i.e., an identical peak serum concentration in each species) and the duration of exposure (i.e., an identical area under the serum concentration-time curve in a finite dosing interval). Using ceftizoxime [(6R,7R)-7-[2-(2-imino-4-thiazolin-4-yl)glyoxylamido]- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 7(2)-(Z)-(O-methyl-oxime)] as a model compound, pharmacokinetic equivalency in mice, rats, monkeys, dogs, and humans was established by selecting a dose for each species that produced similar peak serum concentrations, and by selecting a dosage schedule for each species that produced an equivalent area under the serum concentration-time curve in a 24-h dosing interval. The relationships of animal weight to dose and animal weight to dosing schedule were well described by the power equation Y = aWb, where Y is the dosage variable, W is animal weight, log a is the y-intercept, and b is the slope obtained from the plot of log Y versus log W. Toxicology data for 14 antineoplastic agents were obtained from the literature. The power equation adequately described the relationship between toxic dose and animal weight for most of the compounds, demonstrating the utility of the power equation in the assessment of dosing regimens for toxicity studies as well.
Mordenti
J
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D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001835:Body Weight; D002439:Cefotaxime / Q000008:administration & dosage / Q000031:analogs & derivatives; D015296:Ceftizoxime; D004285:Dogs; D006801:Humans; D007700:Kinetics; D008253:Macaca mulatta; D051379:Mice; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D013045:Species Specificity
D000970:Antineoplastic Agents; D004364:Pharmaceutical Preparations; D015296:Ceftizoxime; D002439:Cefotaxime