Re: “High-Content Screening Identifies New Inhibitors of Connexin 43 Gap Junctions” by Picoli et al. ( Assay Drug Dev Technol. 2019;17:240–248)

Dear Editor,

Iread with interest the recent study by Picoli et al., ¹ which describes the results of in vitro studies of inhibition of connexin 43 (Cx43) gap junctions (GJs) by various approved drugs, including the antimalarial drug mefloquine.

Although mefloquine is now prescribed relatively infrequently to healthy persons owing to concerns for potentially permanent neuropsychiatric adverse effects, which are now the subject of boxed warnings in the United States, Canada, and the European Union, the drug (as a component of THN201) has been investigated by the study's sponsors for repurposing in the treatment of Alzheimer's disease. ²

The data presented by Picoli et al. underscore that such repurposing of mefloquine may prove problematic, owing to the drug's inherent neurotoxicity and its narrow therapeutic window. According to the authors' results (as shown in figure 2A), in a glioblastoma cell line, mefloquine exhibits >50% Cx43 GJ inhibition at 5 μM, but also exhibits >50% neurotoxicity at 10 μM.

This narrow therapeutic window presents particular risk, given that mefloquine exhibits 10-fold variation in volume of distribution, ranging from 5 to 50 L/kg, consistent with heterogeneous population pharmacokinetics. It is possible that significant neuropharmacokinetic variability underlies much of this population heterogeneity, owing to genetic variability in the function of blood–brain barrier transporters, including P-glycoprotein. ³

Both the neuropharmacokinetic heterogeneity of mefloquine and the drug's potentially permanent neuropsychiatric adverse effects have been identified as potential limitations in the repurposing of mefloquine for treatment of other conditions, including progressive multifocal leukoencephalopathy ⁴ and glioblastoma. ⁵

Owing to the drug's narrow therapeutic window and risk of neurotoxicity, caution is needed particularly in the repurposing of mefloquine for indications, such as Alzheimer's disease, which may mask recognition of possible neuropsychiatric adverse effects.