Pharmacokinetics of asundexian with combined CYP3A and P-gp inhibitors and an inducer: Target in vitro and in vivo studies.

Abstract

Asundexian is an oral, direct and reversible inhibitor of activated factor XI (FXIa) in development for the treatment of thromboembolic events. This article summarizes results from preclinical and clinical studies, including identification of enzymes involved in asundexian pharmacokinetics, and evaluation of potential target drug-drug interactions. In vitro studies investigated the substrate characteristics of asundexian towards several cytochrome P450 (CYP) isoforms, hydrolytic enzymes and drug transporters. Inhibition of the amide hydrolysis of asundexian was investigated in vitro for several relevant drugs. Phase 1 studies in healthy male participants investigated the pharmacokinetics (PK) of asundexian upon co-administration of combined inhibitors or an inducer of P-gp and CYP3A4 (itraconazole, verapamil or carbamazepine, respectively, or the moderate CYP3A4 inhibitor fluconazole). The pharmacodynamic (PD) markers are activated partial thromboplastin time and FXIa inhibition. Asundexian was predominantly metabolized via carboxylesterase 1 and, to a lesser extent, via CYP3A4 and is a substrate of P-gp. The asundexian area under the plasma concentration-time curve (AUC) increased by 103% and 75.6% upon combined inhibition of P-gp and strong or moderate inhibition of CYP3A4, respectively, but was unaffected by moderate CYP3A4 inhibition. Combined P-gp and CYP3A4 induction by carbamazepine decreased asundexian AUC by 44.4%. PD is concentration-dependent, thus no differences in maximum responses and recovery commensurate with PK effect(s) were observed. Adverse events were mild and asundexian was well tolerated. The presented studies confirmed that CYP3A4 and P-gp contribute to asundexian metabolism and excretion. Observed effects were in line with data from a previous mass balance study.