title: Predictive value of preclinical toxicology studies for platinum anticancer drugs.
abstract: Rodent and nonrodent toxicology studies are currently expected to support Phase I trials of antineoplastic drugs in the United States. To determine the predictive value of these studies, we initiated a project to compare preclinical and clinical toxicity data within various drug classes. The first class analyzed was the platinum anticancer drugs. Twelve platinum analogues that had both preclinical (mice, rats and/or dogs) and clinical data from matching drug administration schedules were identified. The rodent LD10 (the dose that causes lethality in 10% of treated animals) or dog toxic dose high (a dose that when doubled causes lethality in dogs) correlated well with the human maximally tolerated dose on a mg/m2 basis. For every platinum analogue investigated, one-third the rodent LD10 or one-third the dog toxic dose high in mg/m2 gave a starting dose and a first escalation dose that did not exceed the clinical maximally tolerated dose. The dose-limiting toxicities in patients were previously observed in 7 of 7, 7 of 8, and 9 of 11 mouse, rat, and dog studies, respectively. Our data indicate that mice, rats, and dogs all had value in predicting a safe starting dose and the qualitative toxicities in humans for platinum anticancer compounds. The efficiency of Phase 1 trials could have been improved without sacrificing patient safety by allowing higher starting doses for this drug class than conventionally permitted.
authors.affiliation: Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Clark
authors.forename: P A
authors.initials: PA
authors.lastname: Andrews
authors.forename: D D
authors.initials: DD
authors.lastname: Smith
authors.forename: J J
authors.initials: JJ
authors.lastname: DeGeorge
authors.forename: R L
authors.initials: RL
authors.lastname: Justice
authors.forename: J G
authors.initials: JG
authors.lastname: Beitz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005069:Evaluation Studies as Topic; D006801:Humans; D051379:Mice; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D016037:Single-Blind Method; D013045:Species Specificity; D018675:Toxicity Tests / Q000592:standards
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds