[Pharmacokinetic approach to the improvement of clinical predictability in the preclinical test for antitumor agents].
Clinical predictability of preclinical test for antitumor agents has not been significantly improved even after the use of a human tumor/nude mouse model. Such different antitumor activities between preclinical and clinical tests probably due to the fact that therapeutic used in both tests usually each maximum tolerated dose (MTD), are pharmacokinetically not equivalent. Therefore, we introduced a new concept of "clinically equivalent dose (CED)", which can reproduce in the nude mouse the blood level of a given drug observed with human patients received its therapeutic dose. Treatment of human tumors implanted in the nude mice with CEDs of several drugs exhibited much better correlation with their clinical efficacies than those with MTDs. The feasibility of use of CED predicted by animal scale-up procedure as a therapeutic dose in the preclinical test was discussed.
Inaba
M
M
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000493:pharmacokinetics; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin; D008937:Mitomycins / Q000493:pharmacokinetics; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology
D000970:Antineoplastic Agents; D008937:Mitomycins; D016685:Mitomycin; D004317:Doxorubicin; D005472:Fluorouracil