Metabolic disposition of H3B-8800, an orally available small-molecule splicing modulator, in rats, monkeys, and humans
Creators: name: Rioux, Nathalie
name: Smith, Sherri
name: Colombo, Federico
name: Kim, Amy
name: W. George Lai
name: Nix, Darrell
name: Y. Amy Siu
name: Schindler, Joanne
name: Smith, Peter G.
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Medicine
subject: Physiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Cancer
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: 60506 Virology

description: H3B-8800, a novel orally available modulator of the SF3b complex, which potently and preferentially kills spliceosome-mutant tumor cells, is in clinical development for the treatment of advanced myeloid malignancies. We characterized the pharmacokinetics, metabolism and disposition of H3B-8800 in rats, monkeys and humans.<i>In vitro</i>, H3B-8800 is a substrate of CYP3A4/5, flavin-containing monooxygenases (FMOs) and P-glycoprotein (P-gp), and showed a favorable drug–drug interaction profile as a perpetrator.Following oral dosing of <sup>14</sup>C-H3B-8800 in bile-duct cannulated SD rats, 54.7% of the dosed radioactivity was excreted in the bile, with less found in feces (36.8%). The low amount in urine (3.7%), suggests that renal elimination is a minor pathway of clearance for H3B-8800.In Long-Evans rats, radioactivity derived from <sup>14</sup>C-H3B-8800 was rapidly absorbed, with the highest distribution in the ocular, metabolic/excretory, and gastrointestinal tract tissues. No radioactivity was detected in the central nervous system.Seven metabolites were observed in human plasma following 4 daily doses of 40 mg H3B-8800. H3B-68736 (<i>N</i>-desmethyl), H3B-77176 (<i>N</i>-oxide), and unchanged H3B-8800 were the prominent components in human plasma, at 27.3%, 18.1%, and 33.2%, respectively, of the total drug-related material in a pooled AUC<sub>0–24h</sub> sample. The same 7 metabolites were observed in monkey plasma. H3B-8800, a novel orally available modulator of the SF3b complex, which potently and preferentially kills spliceosome-mutant tumor cells, is in clinical development for the treatment of advanced myeloid malignancies. We characterized the pharmacokinetics, metabolism and disposition of H3B-8800 in rats, monkeys and humans. <i>In vitro</i>, H3B-8800 is a substrate of CYP3A4/5, flavin-containing monooxygenases (FMOs) and P-glycoprotein (P-gp), and showed a favorable drug–drug interaction profile as a perpetrator. Following oral dosing of <sup>14</sup>C-H3B-8800 in bile-duct cannulated SD rats, 54.7% of the dosed radioactivity was excreted in the bile, with less found in feces (36.8%). The low amount in urine (3.7%), suggests that renal elimination is a minor pathway of clearance for H3B-8800. In Long-Evans rats, radioactivity derived from <sup>14</sup>C-H3B-8800 was rapidly absorbed, with the highest distribution in the ocular, metabolic/excretory, and gastrointestinal tract tissues. No radioactivity was detected in the central nervous system. Seven metabolites were observed in human plasma following 4 daily doses of 40 mg H3B-8800. H3B-68736 (<i>N</i>-desmethyl), H3B-77176 (<i>N</i>-oxide), and unchanged H3B-8800 were the prominent components in human plasma, at 27.3%, 18.1%, and 33.2%, respectively, of the total drug-related material in a pooled AUC<sub>0–24h</sub> sample. The same 7 metabolites were observed in monkey plasma.