FDA Montelukast Working Group Studies: Identification of Off-Target Neurological Receptors and Potential Molecular Mechanisms of Drug-Related Neuropsychiatric Adverse Effects (P208)

Monday, November 18, 2024

5:00 PM - 6:30 PM CT

Presenting Author(s)

Jessica J.H. Oliphant

Deputy Director
FDA, NCTR
Benton, Arkansas, United States

Co-Author(s)

Bounleut Phanavanh

NCTR, FDA
Jefferson, Arkansas, United States
Sandeep Kondala, Ph.D.

NCTR, FDA
Jefferson, Arkansas, United States
Svetoslav Slavov, Ph.D.

NCTR, FDA
Jefferson, Arkansas, United States
Elizabeth Jones, Ph.D.

NCTR, FDA
Jefferson, Arkansas, United States
Lisa Pence

NCTR, FDA
Jefferson, Arkansas, United States
Andrew Goodwin, PhD

CDER, FDA
Silver Spring, Maryland, United States
David Klein, Ph.D.

CDER, FDA
Silver Spring, Maryland, United States
Timothy Robison, PhD

CDER, FDA
Silver Spring, Maryland, United States
Li-Rong Yu, Ph.D.

NCTR, FDA
Silver Spring, Maryland, United States

Montelukast (Singulair, CAS #158966-92-8) has been widely used to manage asthma symptoms among millions of adults and pediatrics. Although use has been associated with neuropsychiatric adverse events, 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 abstract is the first public release of findings from the FDA MWG studies.