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

Abstract

1. 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.

2. 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.

3. 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.

4. 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.

5. 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 AUC_0–24h sample. The same 7 metabolites were observed in monkey plasma.

Keywords:

• H3B-8800
• pharmacokinetics
• metabolism
• mass balance
• QWBA

Acknowledgments

The authors want to thank the H3B-8800 team at H3 Biomedicine for fruitful discussions.

Disclosure statement

The authors report no potential conflict of interest.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research was sponsored by H3 Biomedicine.