Evaluation of alpha-difluoromethylornithine as a potential chemopreventive agent: tolerance to daily oral administration in humans
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 pharmac...
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Published in | Cancer epidemiology, biomarkers & prevention Vol. 2; no. 3; p. 243 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.05.1993
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 1055-9965 1538-7755 |