التفاصيل البيبلوغرافية
| العنوان: |
Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL‐286, a novel retinoic acid receptor‐β agonist for treatment of spinal cord injury, in male healthy participants. |
| المؤلفون: |
Goncalves, Maria B., Mant, Tim, Täubel, Jörg, Clarke, Earl, Hassanin, Hana, Bendel, Daryl, Fok, Henry, Posner, John, Holmes, Jane, Mander, Adrian P., Corcoran, Jonathan P. T. |
| المصدر: |
British Journal of Clinical Pharmacology; Dec2023, Vol. 89 Issue 12, p3573-3583, 11p |
| مصطلحات موضوعية: |
SPINAL cord injuries, TRETINOIN, RETINOIC acid receptors, LEUCOCYTES, PHARMACOKINETICS |
| مستخلص: |
Aims: KCL‐286 is an orally available agonist that activates the retinoic acid receptor (RAR) β2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL‐286 in male healthy volunteers to establish dosing to be used in the SCI patient population. Methods: The design was a double blind, randomized, placebo‐controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARβ2 mRNA expression was evaluated in white blood cells. Results: At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration–time curve up to 24 h showing a trend to subproportionality with dose. RARβ2 was upregulated by the investigational medicinal product in white blood cells. Conclusion: KCL‐286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL‐286 as a novel oral treatment for SCI. [ABSTRACT FROM AUTHOR] |
|
Copyright of British Journal of Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
Full Text Finder