AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.
The AAPS journal. 2016 Mar 04 [Epub ahead of print]
Hao Cheng, Zhiliang Xie, William P Jones, Xiaohui Tracey Wei, Zhongfa Liu, Dasheng Wang, Samuel K Kulp, Jiang Wang, Christopher C Coss, Ching-Shih Chen, Guido Marcucci, Ramiro Garzon, Joseph M Covey, Mitch A Phelps, Kenneth K Chan
College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA., Sanofi-Aventis, Malvern, Pennsylvania, USA., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA., Comprehensive Cancer, The Ohio State University, Columbus, Ohio, USA., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA., Comprehensive Cancer, The Ohio State University, Columbus, Ohio, USA., The National Cancer Institute, Rockville, Maryland, USA., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA. ., College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA. .