Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial
| Autor: | J. Andrew Lockton, Richard Eastell, Richard D. Finkelman, Glen Clack, Rosemary A. Hannon, Martin Rimmer, Alan Swaisland |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male medicine.medical_specialty Bone disease Endocrinology Diabetes and Metabolism Osteoporosis Urology Placebo Bone resorption Drug Administration Schedule Bone remodeling chemistry.chemical_compound Double-Blind Method Osteoclast Internal medicine medicine Humans Orthopedics and Sports Medicine Benzodioxoles Enzyme Inhibitors Creatinine business.industry medicine.disease medicine.anatomical_structure Endocrinology chemistry Quinazolines Bone Remodeling business Men's Health Type I collagen Biomarkers |
| Zdroj: | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 25(3) |
| ISSN: | 1523-4681 |
| Popis: | Src is a nonreceptor tyrosine kinase thought to be essential for osteoclast function and bone resorption. We investigated the effect of the orally available Src inhibitor saracatinib (AZD0530) on bone turnover in healthy men. The study was part of a randomized, double-blind, placebo-controlled multiple-ascending-dose phase I trial of saracatinib. Fifty-nine healthy men (mean age 34.6 years) were divided into five cohorts; four with 12 subjects and one with 11 subjects, and randomized within each cohort in the ratio 3:1 to receive a single dose of saracatinib or placebo, respectively, followed 7 to 10 days later with daily doses for a further 10 to 14 days. Dosing levels of saracatinib ascended by cohort (60 to 250 mg). Markers of bone turnover were measured predose and 24 and 48 hours after the initial single dose and immediately before and 24 and 48 hours and 10 to 14 days after the final dose. Data from 44 subjects were included in the analysis. There was a dose-dependent decrease in bone resorption markers [serum cross-linked C-telopeptide of type I collagen (sCTX) and urinary cross-linked N-telopeptide of type I collagen normalized to creatinine (uNTX/Cr)]. At a dose of 250 mg (maximum tolerated dose), sCTX decreased by 88% [95% confidence interval (CI) 84-91%] and uNTX/Cr decreased by 67% (95% CI 53-77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. There were no significant adverse events. We conclude that inhibition of Src reduces osteoclastic bone resorption in humans. Saracatinib is a potentially useful treatment for diseases characterized by increased bone resorption, such as metastatic bone disease and osteoporosis. |
| Databáze: | OpenAIRE |
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