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MISONIQAZOlE: hypoxic cell rad iosensit iser

Review of oral studies so far .. . Studies on the use o f hYPOlic cell radiosensitisers have centred

on the nitroimidazoles and in particular on misonidazole (RO 01.0582, NSC 261 ,0)7 ; Roche). Phase I trials studied optimum dose schedules of misonidazole ranging from weekly and twice weekly doses for )·6 weeks to daily doses for 5-1 days. It was found that dose·limiting neurotoxicity occurred with a Iota] dose of about 128 / ml, but somt protection w.as afforded in those patients taking dexamethasone and phenytoin simultaneously. Phase II studies have involved a total so far of 324 evaluable patients with gliomas. head and neck cance~, brain and hepatic metastases. a nd no n-oat<eJllung cancers

amongOlhers. Reducing the dosage from 2.Sg/ml weekly for 6 weeks to 2.0g/ ml (lowering the total dose from 15g/ ml to 128/m2) reduced the incidence of neuropathy. Some good tumour clearances have been seen and the treatment seems to be about as well tolerated as radiation alone . There are 2 forms of acule toxicity. Gl toxicity - nausea and vomiting - has occurred in 5S % of 226 patients, though radiation-induced toxicity is not easy to distinguish separately. Neurotoxicity, oonsisting of peripheral neuropathy (23 % of 324 cases) and central neurotoxicity (9 % of 324 cases), begins to show as the total doses approaches 10g/ ml, and manifests i!Self as sensory changes, paraesthesia and pain, or confusion, lethargy and decreased mental function . Severe neurotoxicity oocurs in about 3 % of cases (peripheral) to I .S % (central). Toxicity appears more prevalent in the elderly and in the dehydrated. Ototoxicity, fever, rash and allergy have also been reported , but there is no evidence of liver, bone marrow or renal toxici tY,:or loxici ty of any oUier organs so far. Development or further analogues (such as Ro 05-996] the metabolite of misonidazole) wilh less toxicity is the future goal. since the dose required to provide good blood levels of 50- 1 OOf.lS/ml soon totals the upper cumulative dose limit , but in the meantime, ongoing clinical trials with misonidazole are aiming to determine the efficaCY of the drug. Wuscrman. T.II . d al. : Cancer QinicaL Tr i.l1s 4: 7 (No 1. 198 L I

... and the advantages of IV doses An IV form ofmisonidazole (500mg in I 9.7ml saline) has been given to 9 patients, as a single IV infusion ofO.5-S.0g , and to 10 patients as twice weekly doses of 1.5-2 .0g / ml for 5·13 doses. The distribution half-life was S.S min (with distribution volume equivalent to the body water volume). Elimination half-life was 9.3 hours . There was rapid metabolism to desmethylmisonidazole. constituting about 10 % of the total drug plasma level. Just over 25 % of the drug was recovered in the urine. about 15% as the metabolite and 10 % as intact drug. Bile levels never exceeded I % . Peak plasma levels equalled 31 .9)Jg / ml per gram on IV compared with 23)Jg/ mJ for oral dosing. Tumour levels {in melanoma)

6 INPHARMA 9 Mav 1981

showed SO 96 of plasma levels. Five patients on multiple doses experienced nausea/vomiting and 2 others had to stop treatment because of peripheral neuropathy and tinnitus, but no drug-related GI, haematologicaI or neurological effects were seen on Single doses. Two patients suffered a rash. The IV form has the advantage ofprodueing the same blood level as the oral form at a lower dose, thus longer treatment can be given before reaching the toxic total dose. Schwadc. lG. a al .: Cancer O inical Trials 4: JJ(No t . 198 1)

Desmethylmisonidazole: maybe better, maybe not 1 DesmethylmisonidazoJe is Jess lipophilic than its parent oompound and its AUC in theCSF is red uced to a third that of misonidazole, yet the concentration in tumours remains similar to that ofmisonidazole. It would seem likely then. that this drug might produce similar tumou r radiosensitisation, but Jess neurotox icity. Of 13 patients given desmethylmisonidazole up to 12g/ m' total dose, however, 5 patients developed peripheral neuropathy within 25-38 days of starting (moderate severity in 3. mild in 2), which was similar to that observed with misonidazole. Nevertheless. 10 of the 13 patients showed oomplete reliefof primary tumour sympLOms and complete regression ofthe tumour. In the] others. regression was partial. These results warrant a funher study. for they are considerably bener than those seen with misonidazole., Dischc . S. et al. : lIril ish Journal or Rad ioLo~\' H : r S6 (Feb 198 11

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