title: Evaluation of alpha-difluoromethylornithine as a potential chemopreventive agent: tolerance to daily oral administration in humans.
abstract: An initial clinical trial of alpha-difluoromethylornithine given p.o. daily for 6 months was carried out in 27 subjects free of disease following surgery for malignancy or in a defined high-risk group for cancer. The aim was to determine the highest nontoxic dose, principal side effects, and pharmacokinetic parameters. The starting dose was 200 mg/m2/day in divided doses with escalation each month in the absence of toxicity to 6400 mg/m2/day or to the highest nontoxic dose, whichever was lower. When the highest nontoxic dose was reached, this dose was continued to complete 26 weeks of treatment. Twenty-two subjects completed 26 weeks of alpha-difluoromethylornithine treatment of whom 20 reached a nontoxic dose of at least 1600 mg/m2/day. The dose-limiting toxicity was loss of high-tone auditory acuity on an audiogram. Other side effects included diarrhea, fatigue, joint pain, insomnia, and rash. Pharmacokinetics were linear with dose. Area under the plasma concentration x time curve and maximum plasma concentration of alpha-difluoromethylornithine did not predict for development of ototoxicity. The dose for phase II chemoprevention studies should not exceed 1600 mg/m2/day.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: P J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: L
authors.initials: L
authors.lastname: Pendyala
authors.forename: N J
authors.initials: NJ
authors.lastname: Petrelli
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001299:Audiometry; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D000518:Eflornithine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006311:Hearing Disorders / Q000139:chemically induced / Q000175:diagnosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000517:prevention & control* / Q000601:surgery; D012307:Risk Factors; D013997:Time Factors
chemical_list: D000518:Eflornithine