Predictive value of preclinical toxicology studies for platinum anticancerdrugs

Citation
Dl. Clark et al., Predictive value of preclinical toxicology studies for platinum anticancerdrugs, CLIN CANC R, 5(5), 1999, pp. 1161-1167
Citations number
29
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
1078-0432 → ACNP
Volume
5
Issue
5
Year of publication
1999
Pages
1161 - 1167
Database
ISI
SICI code
1078-0432(199905)5:5<1161:PVOPTS>2.0.ZU;2-X
Abstract
Rodent and nonrodent toxicology studies are currently expected to support P hase I trials of antineoplastic drugs in the United States. To determine th e predictive value of these studies, we initiated a project to compare prec linical and clinical toxicity data within various drug classes. The first c lass analyzed was the platinum anticancer drugs. Twelve platinum analogues that had both preclinical (mice, rats and/or dogs) and clinical data from m atching drug administration schedules were identified. The rodent LD,, (the dose that causes lethality in 10% of treated animals) or dog toxic dose hi gh (a dose that when doubled causes lethality in dogs) correlated well with the human maximally tolerated dose on a mg/m(2) basis, For every platinum analogue investigated, one-third the rodent LD,, or one-third the dog toxic dose high in mg/m(2) gave a starting dose and a first escalation dose that did not exceed the clinical maximally tolerated dose. The dose-limiting to xicities in patients were previously observed in 7 of 7, 7 of 8, and 9 of 1 1 mouse, rat, and dog studies, respectively. Our data indicate that mice, r ats, and dogs all had value in predicting a safe starting dose and the qual itative toxicities in humans for platinum anticancer compounds. The efficie ncy of Phase 1 trials could have been improved without sacrificing patient safety by allowing higher starting doses for this drug class than conventio nally permitted.