Preclinical evaluation of ELP-004 in mice.
Jamie L McCallWerner J GeldenhuysLisa J RobinsonMichelle R WittPeter M GannettBjörn C G SöderbergHarry C BlairJonathan SoboloffJohn B BarnettPublished in: Pharmacology research & perspectives (2024)
This study provides a detailed understanding of the preclinical pharmacokinetics and metabolism of ELP-004, an osteoclast inhibitor in development for the treatment of bone erosion. Current treatments for arthritis, including biological disease-modifying antirheumatic drugs, are not well-tolerated in a substantial subset of arthritis patients and are expensive; therefore, new treatments are needed. Pharmacokinetic parameters of ELP-004 were tested with intravenous, oral, and subcutaneous administration and found to be rapidly absorbed and distributed. We found that ELP-004 was non-mutagenic, did not induce chromosome aberrations, non-cardiotoxic, and had minimal off-target effects. Using in vitro hepatic systems, we found that ELP-004 is primarily metabolized by CYP1A2 and CYP2B6 and predicted metabolic pathways were identified. Finally, we show that ELP-004 inhibits osteoclast differentiation without suppressing overall T-cell function. These preclinical data will inform future development of an oral compound as well as in vivo efficacy studies in mice.
Keyphrases
- rheumatoid arthritis
- end stage renal disease
- bone loss
- cell therapy
- high fat diet induced
- chronic kidney disease
- newly diagnosed
- copy number
- stem cells
- prognostic factors
- signaling pathway
- type diabetes
- mesenchymal stem cells
- bone mineral density
- low dose
- high dose
- metabolic syndrome
- patient reported outcomes
- deep learning
- genome wide
- artificial intelligence
- postmenopausal women
- disease activity
- insulin resistance
- patient reported