Improved Preclinical Drug Metabolism and Pharmacokinetics of Pibothiadine (HEC121210), a Novel Hepatitis B Virus Capsid Assembly Modulator

ABSTRACT

1. Pibothiadine (PBD; HEC121120) is a novel hepatitis B virus capsid assembly modulator based on GLS4 (morphothiadine) and has inhibitory activities against resistant strains.

2. To assess the overall preclinical drug metabolism and pharmacokinetics (DMPK) properties of PBD, in vivo pharmacokinetics studies in rats and dogs have been performed along with a series of in vitro metabolism assays.

3. The oral bioavailability of PBD in rats and dogs might be related to its medium permeability in Caco-2 cells and largely be impacted by the pH-dependent solubility. PBD was highly distributed to the liver where the local exposure was 16.4 fold of the system exposure. PBD showed relatively low metabolic rate in recombinant human cytochrome P450 enzymes, whereas low to moderate in vitro clearance in liver microsomes and low (dog) to moderate (rat) in vivo clearance. Furthermore, β-oxidation and dehydrogenation were proposed as the primary metabolic pathways of PBD in rats.

4. Compared to GLS4, the higher systemic exposure of PBD might be attributed to its improved oral absorption and metabolic stability. In addition, the enhanced liver/plasma exposure ratio could further increase the local exposure around the target. These improved DMPK properties might indicate better development of PBD in the clinical phase.

KEYWORDS:

• Pibothiadine
• DMPK
• Oral bioavailability
• Tissue distribution
• Metabolic stability
• Metabolite identification

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Funding

This work was supported by the Enterprise Key Laboratory of Anti-viral Drug Development for Guangdong Province under grant [number 2020B1212070003] and Guangdong Basic and Applied Basic Research Foundation under grant [number 2020A1515111061].