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Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of LXR‐623, a Novel Liver X‐Receptor Agonist, in Healthy Participants
Author(s) -
Katz Arie,
Udata Chandrasekhar,
Ott Elyssa,
Hickey Lisa,
Burczynski Michael E.,
Burghart Peter,
Vesterqvist Ole,
Meng Xu
Publication year - 2009
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270009335768
Subject(s) - liver x receptor , abcg1 , abca1 , pharmacodynamics , agonist , pharmacokinetics , pharmacology , cholesterol , reverse cholesterol transport , medicine , population , endocrinology , chemistry , receptor , transporter , nuclear receptor , lipoprotein , biochemistry , environmental health , transcription factor , gene
Liver X‐receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate—binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR‐623 is a synthetic ligand for LXRs α and β that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending‐dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR‐623 in healthy participants. LXR‐623 was absorbed rapidly with peak concentrations (C max ) achieved at approximately 2 hours. The C max and area under the concentration‐time curve increased in a dose‐proportional manner. The mean terminal disposition half‐life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose‐dependent increase in ABCA1 and ABCG1 expression. The effect of LXR‐623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic‐pharmacodynamic analysis, yielding EC 50 estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system—related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of “target engagement” by an LXR agonist in humans.