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

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 tumours (seven glioblastomas, four recurrent brain tumours) and three patients with oesophageal carcinoma. The doses of MIS administered were usually well tolerated but the principal toxicities observed were peripheral neuropathy as well as nausea and vomiting 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 cerebrospinal fluid. The demethylated product, Ro-05-9963, was detected as the major metabolite. Peak plasma levels were obtained one to four hours after administration of MIS, with a half-life of five to ten hours. Cerebrospinal fluid levels of MIS correlated well with those of the plasma. MIS was mainly excreted as the demethylated metabolite, but less than 40% of the given dose could be recovered. The results obtained suggest that the present MIS dosage for glioblastoma patients results in a low plasma level with no observable therapeutic effect.