LAUSR

I read with interest the recent report by Maraka et al, which described the results of a phase 1 study of temozolomide together with combinations of repurposed memantine, metformin, and mefloquine for the treatment of patients with glioblastoma. I am concerned that the authors’ reported rates of neuropsychiatric adverse effects associated with the use of mefloquine in their study were unexpectedly low, and that certain adverse effects attributed by the authors to memantine actually may represent adverse effects of mefloquine. In the initial doublet arms of the study used to assess the dose-limiting toxicity of each drug, the authors noted that no “intolerable” grade 2 and no grade ≥3 toxic effects (graded according to the National Cancer Institute’s Common Toxicity Criteria [version 4.03]) were attributed to mefloquine among patients who were administered 750 mg of the drug weekly in divided doses. However, only 3 subjects received mefloquine in the initial doublet arms, in comparison with 8 patients who received memantine and 9 who received metformin. The authors did not explain the noticeable discrepancy in sample sizes across these study arms, nor did they acknowledge that this served to reduce the power to identify dose-limiting toxicities from mefloquine compared with the other 2 study drugs. Doses of 750 mg of mefloquine administered over 1 to 3 days have been well studied in other settings for the drug’s antimalarial indication. For example, in a blinded randomized trial of a loading dose of 750 mg of mefloquine administered over 3 days, it was reported that 17.8% of patients reported depression, 6.7% reported feeling dizzy, and 8.9% reported problems with coordination at day 4. At the end of week 1, 38% of patients reported ≥1 neuropsychiatric symptoms, including 22% of patients who reported insomnia and 9% who reported abnormal dreams, described as “often terrifying nightmares with technicolor clarity, which were vividly remembered days later.” With the use of mefloquine, even at the lower dose of 250 mg weekly that previously was commonly used for the prevention of malaria, neuropsychiatric adverse effects including headache, abnormal dreams, dizziness, anxiety, depression, insomnia, and visual disturbances graded subjectively as “moderate” were reported in 37% of patients, and adverse effects graded as “severe” were reported in 5%. Given the common incidence of dizziness at the 750-mg weekly dose of mefloquine used in the study by Maraka et al, the authors could not exclude the possibility that these adverse effects, which were attributed to memantine at a daily dose of 20 mg in the mefloquine-memantine triplet arm and to a 10-mg daily dose in the mefloquine-memantine-metformin quadruplet arm, were in fact not actually due to mefloquine. Drug regulators now warn that neuropsychiatric adverse effects from mefloquine, including those as seemingly benign as abnormal dreams, must be considered prodromal to a “more serious event,” a euphemism for the permanent adverse effects that may occur with continued use of the drug. Mefloquine is an idiosyncratic neurotoxicant, and may cause permanent neuropsychiatric effects including dizziness, tinnitus, and vertigo as a result of neurotoxicity within brainstem nuclei. Although even permanent dizziness and related neuropsychiatric adverse effects caused by mefloquine may appear to be tolerable within the context of the treatment of a life-threatening condition, given increasing interest in the repurposing of mefloquine and related gap-junction blockers, including for the treatment of neuropathy and the prevention and treatment of neurocognitive disorders in patients with Alzheimer disease, ensuring the accurate attribution of adverse effects from combination drugs containing mefloquine is critical to prelicensing safety studies and for informing appropriate risk-benefit considerations for these proposed indications.