Phase I and pharmacokinetic study of tirapazamine (SR 4233) administered every three weeks

Suresh Senan*, Roy Rampling, Martin A. Graham, Peter Wilson, Hernani Robin, Nils Eckardt, Nora Lawson, Alex McDonald, Reinhard Von Roemeling, Paul Workman, Stanley B. Kaye

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Tirapazamine (SR 4233; 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide) is a bioreductive agent exhibiting up to 200 x greater toxicity for hypoxic cells as compared to oxygenated cells. In murine studies, a selective increase in tumor kill was observed when tirapazamine was coadministered with other agents, notably cisplatin. A Phase I study of single-agent tirapazamine administered i.v. every 3 weeks was conducted to determine the toxicity of a schedule for use with systemic chemotherapy. A total of 28 patients were given 50 courses of tirapazamine at doses ranging from 36-450 mg/m2. No tumor responses were observed. Reversible deafness and tinnitus were dose-limiting, with ototoxicity observed in 1 of 6 patients treated at 330 mg/m2, 1 of 4 patients treated at 390 mg/m2, and 3 of 3 patients treated at 450 mg/m2. Muscle cramps, nausea, and vomiting were also observed. Pharmacokinetic studies revealed a greater than dose-proportional increase in the area under the plasma concentration x time curve (AUCs) of the two major metabolites. Patients who developed ototoxicity generally showed higher plasma AUC values for the parent drug and metabolites. The mean plasma tirapazamine AUC at 330 mg/m2 was 1026.5 μg/ml x min (range 863.8-1252.3), but no pharmacokinetic data are available for the solitary patient who developed otoxicity at this dose level. These AUC values were in the (estimated) range required for therapeutic effect in murine studies. Ototoxicity was not observed when the AUC of tirapazamine was equal to or less than 1252 μg/ml x min. The dose of 330 mg/m2 was therefore chosen as an appropriate level for combination chemotherapy studies.

Original languageEnglish
Pages (from-to)31-38
Number of pages8
JournalClinical Cancer Research
Volume3
Issue number1
Publication statusPublished - 26 Feb 1997

Cite this

Senan, S., Rampling, R., Graham, M. A., Wilson, P., Robin, H., Eckardt, N., ... Kaye, S. B. (1997). Phase I and pharmacokinetic study of tirapazamine (SR 4233) administered every three weeks. Clinical Cancer Research, 3(1), 31-38.