Preclinical metabolism and disposition of an orally bioavailable macrocyclic FXIa inhibitor

Abstract

1. FXIa-6f is a high affinity, orally bioavailable macrocyclic FXIa inhibitor with antithrombotic activity in preclinical species.

2. The objectives of this study were to characterize the in vitro metabolism, determine circulating metabolites in pre-clinical species, and examine the disposition of the compound in a bile duct-cannulated rat study (BDC) study to inform clinical development of the compound and the medicinal chemistry approach to identify molecules with improved properties.

3. Across species, metabolic pathways included several oxidative metabolites, including hydroxylated metabolites on the macrocycle or P1 region, descarbamoylation of the methyl carbamate side chain, and a glutathione conjugate on the 2,6-difluoro-3-chlorophenyl ring.

4. In BDC rat, the absorbed dose of [³H]FXIa-6f was cleared mainly by metabolism, with excretion of drug-related material in the bile, mostly as metabolites.

5. In all preclinical species, the parent drug was the primary drug-related component in circulation, but the species differences in the metabolic pathways observed in vitro were reflected in the plasma, where M6, a descarbamoylated metabolite, was more prominent in rat plasma, and M9, a hydroxylated metabolite, was more prominent in monkey plasma. Based on the available data, the human metabolism appears to be most similar to monkey.

Keywords:

• Oxidative cleavage of carbamate
• bioactivation
• oxidative defluorination
• glutathione conjugates
• factor XIa inhibitor
• LC/MS
• metabolism
• P450

Acknowledgments

The authors thank Chris Freeden and Pamela Abraham in the in vivo study group (TSU) at Bristol Myers Squibb Co. for conducting the in-life portion of the radiolabeled rat study. Thanks to Yanou Yang and Hong Cai for in vitro incubations and to Weiping Zhao for conducting the covalent binding experiments. Thanks to Atsu Apedo for confirming M9 to be a metabolite using orthogonal LC method. Thanks to Laura L. Custer for carrying out the Ames Assay for FXIa-6f and M6. The authors thank Ellen Kick and Michael W. Sinz for discussion and review of the manuscript.

Disclosure statement

Authors are employees or former employees of Bristol Myers Squibb and stock-holders.