Misonidazole as a radiosensitizer in the radiotherapy of glioblastomas and oesophageal cancer. Pharmacokinetic and clinical studies

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Abstract
Since May 1978 the hypoxic-cell radiosensitizer, misonidazole (MIS), has been under clinical investigation in a phase III trial with multiple doses of the drug in 11 patients with brain tumors (7 glioblastomas, 4 recurrent brain tumors) and 3 patients with esophageal carcinoma. The doses of MIS administered were usually well tolerated but the principal toxicities observed were peripheral neuropathy as well as nausea and vomiting in the glioblastoma patients. The neuropathy was completely reversible. The incidence of neuropathy was not related to the pharmacological parameters of plasma level or half-life. Pharmacological assessment by high-pressure liquid chromatography included assays of plasma, urine and CSF. The demethylated product, Ro-05-9963, was detected as the major metabolite. Peak plasma levels were obtained 1-4 h after administration of MIS, with a half-life of 5-10 h. CSF levels of MIS correlated well with those of the plasma. MIS was mainly excreted as the demethylated metabolite, but < 40% of the given dose could be recovered. The present MIS dosage for glioblastoma patients may result in a low plasma level with no observable therapeutic effect.