Misonidazole with dexamethasone rescue: an escalating dose toxicity study.

Area of Science:

• Neuro-oncology
• Clinical Pharmacology

Background:

• Misonidazole (MISO) and desmethylmisonidazole (DMM) neurotoxicity limits clinical use.
• Dexamethasone (DEXA) showed preliminary protective effects against MISO-induced peripheral neuropathies (PN) in prior studies.
• DEXA did not impact MISO pharmacokinetics previously.

Purpose of the Study:

• To investigate the efficacy of Dexamethasone (DEXA) in mitigating misonidazole (MISO) induced neurotoxicity.
• To evaluate the safety and tolerability of escalating MISO doses when co-administered with DEXA.

Main Methods:

• 16 patients received escalating doses of MISO (13.5–17.5 gm/M2) over 3 weeks.
• DEXA (2 mg t.i.d.) was administered 3 days prior to MISO and throughout treatment.
• All patients received palliative radiation therapy.

Main Results:

• No neurotoxicity observed at 13.5 gm/M2 MISO.
• One case of Grade I PN occurred in 4 patients at 15.5 gm/M2 MISO.
• No further PN incidence was observed in 6 additional patients at 15.5 gm/M2 MISO; patients are now being entered at 17.5 gm/M2.

Conclusions:

• DEXA appears to reduce the incidence of MISO-induced peripheral neuropathy.
• The combination of DEXA and MISO at escalating doses shows promise for improved MISO tolerability in cancer treatment.