Preclinical Metabolism and Disposition of SB939 (Pracinostat), an Orally Active Histone Deacetylase Inhibitor, and Prediction of Human Pharmacokinetics

Abstract

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 M) but inhibited 2C19 (IC 50 ‫؍‬ 5.8 M). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between ϳ84 and 94%. The blood-toplasma ratio was ϳ1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l ⅐ h ؊1 ⅐ 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 ϳ3% 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.

Histone Deacetylase Inhibitors as Therapeutic Agents for Cancer Therapy: Drug Metabolism and Pharmacokinetic Properties

“…The human PK of Pracinostat was simulated with the Simcyp ADME simulator (Jamei et al, 2009) using the physico-chemical and in vitro ADME data. The simulated PK profiles were in good agreement with the observed mean data, and the mean oral clearance and AUCs were predicted reasonably well (within 2 fold of observed data) (Jayaraman et al, 2011). Furthermore, simulations of drug-drug interactions (DDI) of Pracinostat in humans with the potent CYP3A inhibitor and inducers, ketoconazole and rifampicin, respectively, and with omeprazole (substrate of 2C19) showed lack of potential DDI at the clinically relevant dose of 60 mg (Jayaraman et al, 2011).…”

“…Pracinostat was found to selectively accumulate in tumors which correlated well with increased and prolonged acetylation levels in tumor which, in turn correlated with high tumor growth inhibition in mice (Novotny-Diermayr et al, 2011). Preclinical ADME of Pracinostat was characterized by: a) in in vitro liver microsomal stability studies, Pracinostat was most stable in human and dog, moderate in mouse, and least stable in rat; b) uniform PPB of 84-94% in preclinical species and humans; c) was metabolized mainly by human CYP3A4 and 1A2; d) did not inhibit the major human CYPs except moderate inhibition of 2C19 (~ 6 µM); e) lack of significant induction of human CYP3A4 and 1A2 in vitro; f) metabolite identification studies using liver microsomes showed the formation of N-deethylation and bis-N-deethylation as major metabolites in addition to minor oxidative products; g) a glucoronidation product of SB939 was found as the major metabolite in rat urine following oral dosing; h) PK: high systemic clearance of 9.2, 4.5 and 1.5 L/h/kg in mice, rat and dog, respectively and high volume of distribution (V ss ranged between 1.7 to 4.2 L/kg) in preclinical species; i) moderate F in mice and dogs and poor in rats (Jayaraman et al, 2011). In PK/PD studies in HCT116 xenograft models, studying the relationship between tumor growth inhibition and the PK/PD indices such as AUC/IC 50,HCT116 , C max / IC 50,HCT116 , and time above IC 50,HCT116 , Pracinostat was found to have the highest PK/PD ratios for all the three PK/PD parameters when compared to Vorinostat, Panabinostat and Belinostat (figure 1) (Jayaraman et al, 2009).…”

“…Pracinostat showed linear allometric relationships for V ss and CL in preclinical species. Prediction of human PK parameters using allometry indicated oral exposures would be achieved in humans with an acceptable t 1/2 which, was subsequently found to be consistent with the observed data from cancer patients (Jayaraman et al, 2011). The human PK of Pracinostat was simulated with the Simcyp ADME simulator (Jamei et al, 2009) using the physico-chemical and in vitro ADME data.…”

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

“…In this study, we tested the in vitro and in vivo antiplasmodial efficacies of a new, orally bioavailable, hydroxamate-based HDAC inhibitor undergoing clinical trials for cancer (35,47,52,65,67). SB939 (pracinostat; S*BIO), a pan-HDAC inhibitor acting on class I, II, and IV HDACs (47,65), has a longer in vivo half-life (t 1/2 of 2.4 h) than those of other hydroxamate-based HDAC inhibitors, such as SAHA (t 1/2 of 0.75 h) ( Table 1).…”

Modern methodologies and tools for human hazard assessment of chemicals

“…It also provides a basis to develop in vitro to in vivo extrapolations (IVIVE) and to predict potential interactions between compounds, which gives a basis to take into account TK interactions for hazard characterisation of multiple compounds (chemical mixtures) (Coecke et al, 2006;Chen et al, 2011;Jayaraman et al, 2011;Kumar et al, 2011;Abass et al, 2013;EFSA, 2013). It also provides a basis to develop in vitro to in vivo extrapolations (IVIVE) and to predict potential interactions between compounds, which gives a basis to take into account TK interactions for hazard characterisation of multiple compounds (chemical mixtures) (Coecke et al, 2006;Chen et al, 2011;Jayaraman et al, 2011;Kumar et al, 2011;Abass et al, 2013;EFSA, 2013).…”