Deputy Director FDA, NCTR Benton, Arkansas, United States
Montelukast (Singulair®, CAS #158966-92-8) has been widely used by millions of pediatrics and adults to manage asthma symptoms, along with increased off-label use, including management of COVID-19 and migraines; however, use has been associated with concern for neuropsychiatric adverse events, which has been a global hot topic of discussion by many patient advocates, health care providers, media, lawmakers, industry, and regulators. Nevertheless, a direct link between montelukast exposure and precipitation of neuropsychiatric-related events has not been clearly established, and potential mechanisms of drug-related effects on the central nervous system (CNS) have remained largely unknown. Following the 2019 FDA Advisory Committee Meeting related to this topic, the FDA Montelukast Working Group (MWG) was established to investigate potential for drug-related CNS effects, with the first of several studies being identification of potential CNS targets of montelukast that could contribute to neuropsychiatric safety concerns. Secondary pharmacology studies were conducted using radioligand binding assays and functional assessments, which identified several candidate off-target G-protein coupled receptors (GPCRs) and neurotransmitter transporters expressed in the brain. Emerging data from confirmatory pharmacology studies in primary human CNS cells treated with montelukast and endogenous receptor ligands provide further insight into potential molecular mechanisms of drug-related CNS effects. A pharmacokinetic model mimicking clinically relevant exposure levels in rats was also developed to evaluate in montelukast-related CNS effects, drug exposure levels, and CNS accumulation potential in vivo. This report is the first public release of findings from the FDA MWG studies.
