Initial pharmacology and toxicology of intravenous desmethylmisonidazole

C. Norman Coleman, Todd H. Wasserman, Theodore L. Phillips, John M. Strong, Raul C. Urtasun, James G. Schwade, Richard J. Johnson, Gunar Zagars

Research output: Contribution to journalArticlepeer-review

Abstract

Since January 1981, 52 patients have entered the Radiation Therapy Oncology Group Phase I trial with intravenous (i.v.) desmethylmisonidazole (DMM). DMM is less lipophilic than misonidazole (MISO) and theoretically will be less neurotoxic due to lower penetration into neural tissue and more rapid elimination. The drug is administered intravenously to achieve the maximum drug concentration in tumor for a given dose. The protocol slowly escalates the total dose of drug administered. At this time the planned dose on the three week schedule is l g/m2 five times per week to a total of 15g/m2', and on the seven week schedule is 1.258/m2 twice weekly to a total dose of 17.5g/m2. The preliminary plasma pharmacokinetic data demonstrates high peak plasma levels within five minutes of the end of the drug infusion. Compared to MISO the percent of DMM excreted in the urine is increased, 63% vs 10%, and the elimination half-life is decreased: DMM, i.v. 5.3h; MISO, i.v. 9.3h; MISO, oral 10 to 13h. Neurotoxicity has been been observed in approximately 30% of patients given a cumulative dose of > l lg/m2. This is in comparison to a 50% incidence in the RTOG Phase 1 study with oral MISO at doses of 12g/m2. There is not sufficient data to evaluate the relationship between neurotoxicity and drug exposure. Further patient accrual on this study is required to better define the properties of DMM.

Original languageEnglish (US)
Pages (from-to)371-375
Number of pages5
JournalInternational journal of radiation oncology, biology, physics
Volume8
Issue number3-4
DOIs
StatePublished - 1982

Keywords

  • DNesmethylmisonidazole
  • Pharmacology
  • Radiosensitizers

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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