Metabolic disposition of H3B-8800, an orally available small-molecule splicing modulator, in rats, monkeys, and humans

Xenobiotica. 2020 Sep;50(9):1101-1114. doi: 10.1080/00498254.2019.1709134. Epub 2020 Jan 6.


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.In vitro, 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 14C-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 14C-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 (N-desmethyl), H3B-77176 (N-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 AUC0-24h sample. The same 7 metabolites were observed in monkey plasma.

Keywords: H3B-8800; QWBA; mass balance; metabolism; pharmacokinetics.

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism*
  • Bile / metabolism
  • Biological Availability
  • Feces / chemistry
  • Haplorhini
  • Humans
  • Piperazines / metabolism*
  • Pyridines / metabolism*
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Tissue Distribution


  • Antineoplastic Agents
  • H3B-8800
  • Piperazines
  • Pyridines