(172) INTRAVENOUS MISONIDAZOLE (NSC 261037)

J.G. Schwade, M.D.l, J.M. Strong, Ph.D.*, and D. Gangji, M.D.3

lRadiation Oncology Granch 2Laboratory Pharmacology

3Pediatric Oncology Branch National Cancer Institute, NIH

Bethesda, Maryland 20205

Misonidazole is a 2-nitroimidazole derivative currently undergoing clinical trials as a hypoxic cell radiation sensitizer. Trials to date have been conducted with oral administration only. Toxicity with the oral formulation consists primarily of gastrointestinal disturbance and sensory peripheral neuropathy, thought to be related to the total dose administered and time of exposure. CNS toxicity has also been reported. The plasma half-life after oral administration is also long (12-14 hours), and absorp- tion and plasma levels differ greatly from patient to patient.

Because it was thought that pharmacokinetic advantages resulting from intravenous administration might circumvent toxicities seen with the oral compound, the Radiation Oncology Branch, NCI, initiated toxicity and pharma- cokinetic studies with an intravenous preparation.

9 patients received single intravenous doses ranging from 266-2650 mg/m2, Samples were assayed by gas chromatography or mass spectrometry. Mean plasma half-life was 8.6 hours (8.0-9.8). Higher peak plasma levels were achieved with the intravenous administration compared to oral on a dose equivalent basis. 1.5 gm/m2 given intravenously yielded the effective plasma level of 100 ug/ml, in contrast to 2.5 gm/m2 or more needed with the oral preparation to achieve the same level. No gastrointestinal or neurological toxicity was observed with sin le doses of 1.5 gm/m !!

I.V. doses. In addition, 3 patients received bi-weekly for 3-5 weeks. No significant toxicity was encountered.

No dose build-up was observed. In one patient bile excretion kinetics were performed. In another patient, pleural fluid kinetics were determined. In 1 patient taking Dilantin, a markedly shorter plasma half-lives were seen (3 hours). Implication of this observation and detailed kinetics will be discussed.

(173) PHARMACOKINETICS OF INTRAVENOUS METRONIDAZOLE: A SENSITIZER OF HYPOXIC TUMOR CELLS.

Urtasun, R., Rabin, H., Partington, J., Koziol, D.

Cross Cancer Institute and University of Alberta, Edmonton, Alberta

As an extension of the studies on the clinical use of nitroimidazoles as radiosensitizers, single dose pharmacokinetics of intravenous metronidazole (M) (500 mg/lOO ml vials) were examined in 8 consenting patient volunteers. Single doses of 0.5, 1.0, 1.5 or 2.0 g (278 to 1212

192 ASTR 21st Annual Meeting