Safety, pharmacokinetics, and pharmacodynamics of single doses of LXR-623, a novel liver X-receptor agonist, in healthy participants.

Abstract

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 alpha and beta 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.

• Authors: Arie Katz, Chandrasekhar Udata, Elyssa Ott, Lisa Hickey, Michael E Burczynski, Peter Burghart, Ole Vesterqvist, Xu Meng
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 49 Issue 6 Pg. 643-9 (Jun 2009) ISSN: 0091-2700 [Print] England
• PMID: 19398602 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• ABCA1 protein, human
• ABCG1 protein, human
• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters
• DNA-Binding Proteins
• Liver X Receptors
• Orphan Nuclear Receptors
• Receptors, Cytoplasmic and Nuclear

Topics

• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters (genetics)
• Adult
• Central Nervous System (drug effects)
• DNA-Binding Proteins (agonists)
• Female
• Gene Expression (drug effects)
• Humans
• Liver X Receptors
• Male
• Middle Aged
• Orphan Nuclear Receptors
• Receptors, Cytoplasmic and Nuclear (agonists)
• Young Adult