Pharmacokinetics, mass balance, metabolism, and excretion of the liver-targeted acetyl-CoA carboxylase inhibitor PF-05221304 (clesacostat) in humans

Abstract

1. The disposition of the hepatoselective ACC inhibitor PF-05221304 (Clesacostat) was studied after a single 50-mg oral dose of [14C]-PF-05221304 to healthy human subjects.

2. Mass balance was achieved with 89.9% of the administered dose recovered in urine and faeces, over the 11-day study period. The total administered radioactivity excreted in faeces and urine was 81.7 and 8.2%, respectively. Unchanged PF-05221304 accounted for 35.6% of the radioactive dose in faeces, suggesting ∼64% of the administered dose was absorbed.

3. PF-05221304 was principally metabolised via oxidative and reductive pathways involving: (a) N-dealkylation, (b) isopropyl group monohydroxylation to yield enantiomeric metabolites (M2a and M2b), (c) hydroxylation on the 3-azaspiro[5.5]undecan-8-one moiety to metabolites M5 and 519c, and (d) carbonyl group reduction to enantiomeric alcohol metabolites M3, and M4. Secondary metabolites (521a, 521b, and 533), derived from a combination of oxidation and reduction of the primary metabolites accounted for ∼14.8% of the dose. In plasma, unchanged PF-05221304 represented 96.1% circulating radioactivity. Metabolites M1, M2b, and M2a represented 1.94, 1.76, and 0.18% of circulating radioactivity, respectively.

4. Overall, these data suggest that PF-05221304 is well absorbed in humans and eliminated largely via phase I metabolism.

Keywords:

• Clesacostat
• acetyl-CoA carboxylase
• human
• mass balance
• metabolite
• cytochrome P450

Acknowledgments

The authors would like to thank the participants of the FIH study. We acknowledge Edel Evard and Aaron Smith for the synthesis of PF-05221304 metabolites. We also acknowledge Jie Jin Shen and Santos Carvajal-Gonzalez for assistance in constructing Figure 2. The work received no external funding.

Disclosure statement

The authors report no declarations of interest. All authors are employees of Pfizer and some of the authors are shareholders in Pfizer Inc. TEB was an employee of Pfizer Inc. during part of this study.

Additional information

Funding

This study was sponsored by Pfizer.