Dose selection as it pertains to testing a prodrug in carcinogenicity bioassays.
Toxicologists need more information than is usually available in the early stages of development of a drug in order to choose proper dose levels for testing in the bioassays. The approach most likely to result in successful bioassays involves an early multidisciplinary effort in which there is pharmacokinetic characterization of the test material in both rats and mice. Preliminary 3 month studies are desirable. Periodic sampling of plasma is essential to detect possible non-linear kinetics (as in the example we report herein) reflected as accumulation of the test material or metabolites. This is true regardless of the test substance. However, if one tests prodrugs it may be particularly helpful to know if chemical or enzymatic conversion of the prodrug is linear and if there is reversion to prodrug or other abberant metabolism. Failure to rule out these possibilities could result in subsequent clinically irrelevant organ damage or could compromise longevity or the interpretation of results in lifetime studies. Pharmacokinetic considerations are as valid as the more traditional biologic or morphologic end points used to estimate maximum tolerated or no-effect dose levels.
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D007700:Kinetics; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced*; D051381:Rats
D002273:Carcinogens