Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase inhibitor, and prediction of human pharmacokinetics

Jayaraman, Ramesh, Reddy, Venkatesh P., Pasha, Mohammed Khalid, Wang, Haishan, Sangthongpitag, Kanda, Yeo, Pauline, Hu, Chang Yong, Wu, Xiaofeng, Xin, Liu, Goh, Evelyn, New, Lee Sun and Ethirajulu, Kantharaj (2011) Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase inhibitor, and prediction of human pharmacokinetics. Drug Metabolism and Disposition, 39 12: 2219-2232. doi:10.1124/dmd.111.041558


Author Jayaraman, Ramesh
Reddy, Venkatesh P.
Pasha, Mohammed Khalid
Wang, Haishan
Sangthongpitag, Kanda
Yeo, Pauline
Hu, Chang Yong
Wu, Xiaofeng
Xin, Liu
Goh, Evelyn
New, Lee Sun
Ethirajulu, Kantharaj
Title Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase inhibitor, and prediction of human pharmacokinetics
Journal name Drug Metabolism and Disposition   Check publisher's open access policy
ISSN 0090-9556
1521-009X
Publication date 2011-12
Sub-type Article (original research)
DOI 10.1124/dmd.111.041558
Volume 39
Issue 12
Start page 2219
End page 2232
Total pages 14
Place of publication Bethesda, MD, United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Collection year 2012
Language eng
Formatted abstract
The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino) ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat. The major metabolites formed in human liver microsomes were also observed in preclinical species. Human cytochrome P450 (P450) phenotyping showed that SB939 was primarily metabolized by CYP3A4 and CYP1A2. SB939 did not significantly inhibit human CYP3A4, 1A2, 2D6, and 2C9 (>25 µM) but inhibited 2C19 (IC50 = 5.8 µM). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between ~84 and 94%. The blood-to plasma ratio was ~1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l • h-1 • kg-1 and high volume of distribution at steady state (>0.6 l/kg) of 3.5, 1.7, and 4.2 l/kg in mouse, rat, and dog, respectively. The oral bioavailability was 34, 65, and ~3% in mice, dogs, and rats, respectively. The predicted oral PK profile and parameters of SB939, using Simcyp and allometric scaling, were in good agreement with observed data in humans. Simcyp predictions showed lack of CYP3A4 and 2C19 drug-drug interaction potential for SB939. In summary, the preclinical ADME of SB939 supported its preclinical and clinical development as an oral drug candidate.
Keyword In Vitro
Hydroxamic Acid
Drug Metabolism
Phase I
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Medicine Publications
 
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