title: Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase inhibitor, and prediction of human pharmacokinetics.
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 (IC(50) = 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.
authors.affiliation: S*BIO Pte Ltd., 1 Science Park Road, no. 05-09, The Capricorn, Singapore Science Park II, Singapore 117528.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Jayaraman
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Pilla Reddy
authors.forename: Mohammed Khalid
authors.initials: MK
authors.lastname: Pasha
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.forename: Pauline
authors.initials: P
authors.lastname: Yeo
authors.forename: Chang Yong
authors.initials: CY
authors.lastname: Hu
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wu
authors.forename: Liu
authors.initials: L
authors.lastname: Xin
authors.forename: Evelyn
authors.initials: E
authors.lastname: Goh
authors.forename: Lee Sun
authors.initials: LS
authors.lastname: New
authors.forename: Kantharaj
authors.initials: K
authors.lastname: Ethirajulu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry
chemical_list: D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; C557525:SB939 compound; D003577:Cytochrome P-450 Enzyme System