Pharmacokinetics, pharmacodynamics, and safety of asundexian in healthy Chinese and Japanese volunteers, and comparison with Caucasian data.

There is an unmet clinical need for effective anticoagulant therapies for the management of thromboembolic diseases that are not associated with a relevant risk of bleeding. Asundexian (BAY 2433334) is an oral, direct, small-molecule inhibitor of activated factor XI (FXIa). Phase I data from healthy Caucasian male participants indicated predictable pharmacokinetic (PK) and pharmacodynamic (PD) profiles and no clinically relevant bleeding-related adverse events (AEs). Reported here are data from two phase I, randomized, placebo-controlled, single- and multiple-dose escalation studies of asundexian conducted in 60 healthy men: 24 Japanese and 36 Chinese. Baseline characteristics were comparable between the treatment groups. All treatment-emergent AEs were mild, with no serious AEs or AEs of special interest reported. Systemic exposure to asundexian increased dose proportionally after single or multiple dosing, with relatively low accumulation following multiple once-daily dosing in both Chinese and Japanese volunteers. Asundexian induced dose-dependent prolongation of activated partial thromboplastin time and inhibition of FXIa activity, with no effects on prothrombin time or FXI concentration in Japanese participants. There were no clinically relevant interethnic differences in PK profile across the Japanese, Chinese, and Caucasian (data from the previous phase I study) participants and no clinically relevant difference in PD response between Japanese and Caucasian participants.

No Influence of Asundexian on Cardiac Repolarization.

Inhibition of activated factor XI reduces thrombogenesis while maintaining physiological hemostasis, with the expectation of reduced bleeding risk compared with standard of care in the clinical setting. Asundexian (BAY 2433334), an activated factor XI inhibitor, is in clinical development for the prevention of thromboembolic events. The effect of asundexian and its plasma metabolite M10 on cardiac repolarization and potential interactions with the hNav1.5 sodium, hCav1.2 calcium, and human ether-à-go-go-related gene (hERG) potassium channels was investigated in vitro. Additionally, asundexian effects on cardiac parameters and electrocardiogram were examined in telemetered beagle dogs. A randomized, placebo-controlled, 4-way crossover, thorough QT study in healthy adults evaluated the influence of 50 and 150 mg of asundexian on the corrected QT interval, including 400 mg of moxifloxacin as positive control. Across all studies, asundexian and M10 were not associated with any effects on cardiac repolarization. The largest in vitro effects of asundexian (approximately 20% inhibition) were seen for hCav1.2 and hERG. Throughout the thorough QT study, the upper limits of the one-sided 95% confidence interval of placebo-corrected mean changes from baseline in Fridericia corrected QT for 50 and 150 mg of asundexian were below Δ = 10 milliseconds. Asundexian demonstrated favorable safety and tolerability profiles.

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

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Assessment of the CYP3A4 Induction Potential by Carbamazepine: Insights from Two Clinical DDI Studies and PBPK Modeling.

In the past, rifampicin was well-established as strong index CYP3A inducer in clinical drug-drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically-based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs during drug development. CYP3A4 induction properties and the safety profile of carbamazepine were investigated in two open-label, fixed sequence, crossover clinical pharmacology studies in healthy volunteers using midazolam as a sensitive index CYP3A4 substrate. Carbamazepine was up-titrated from 100 mg twice daily (b.i.d.) to 200 mg b.i.d., and to a final dose of 300 mg b.i.d. for 10 consecutive days. Mean area under plasma concentration-time curve from zero to infinity (AUC(0-∞)) of midazolam consistently decreased by 71.8% (ratio: 0.282, 90% confidence interval (CI): 0.235-0.340) and 67.7% (ratio: 0.323, 90% CI: 0.256-0.407) in study 1 and study 2, respectively. The effect was adequately described by an internally developed PBPK model for carbamazepine which has been made freely available to the scientific community. Further, carbamazepine was safe and well-tolerated in the investigated dosing regimen in healthy participants. The results demonstrated that the presented design is appropriate for the use of carbamazepine as alternative inducer to rifampicin in DDI studies acknowledging its CYP3A4 inductive potency and safety profile.

Metabolism and Disposition of the Novel Oral Factor XIa Inhibitor Asundexian in Rats and in Humans.

BACKGROUND AND OBJECTIVES: Current anticoagulants pose an increased risk of bleeding. The development of drugs targeting factor XIa, like asundexian, may provide a safer treatment option. A human mass­balance study was conducted to gain a deeper understanding of the absorption, distribution, metabolism, excretion, and potential for drug-drug interaction of asundexian. Additionally, an overview of the biotransformation and clearance pathways for asundexian in humans and bile-duct cannulated (BDC) rats in vivo, as well as in vitro in hepatocytes of both species, is reported. METHODS: The mass balance, biotransformation, and excretion pathways of asundexian were investigated in six healthy volunteers (single oral dose of 25 mg [14C]asundexian) and in BDC rats (intravenous [14C]asundexian 1 mg/kg). RESULTS: Overall recovery of radioactivity was 101% for humans (samples collected up to 14 days after dosing), and 97.9% for BDC rats (samples collected in the 24 h after dosing). Radioactivity was mainly excreted into feces in humans (80.3%) and into bile/feces in BDC rats (> 94%). The predominant clearance pathways in humans were amide hydrolysis to metabolite M1 (47%) and non-labeled M9 with subsequent N-acetylation to M10; oxidative biotransformation was a minor pathway (13%). In rats, hydrolysis of the terminal amide to M2 was the predominant pathway. In human plasma, asundexian accounted for 61.0% of total drug-related area under the plasma concentration-time curve (AUC); M10 was the major metabolite (16.4% of the total drug-related AUC). Excretion of unmetabolized drug was a significant clearance pathway in both species (human, ~ 37%; BDC rat, ~ 24%). The near-complete bioavailability of asundexian suggests negligible limitations on absorption and first-pass metabolism. Comparison with radiochromatograms from incubations with human or rat hepatocytes indicated consistency across species and a good overall in vitro/in vivo correlation. CONCLUSIONS: Similar to preclinical experiments, total asundexian-derived radioactivity is cleared quantitatively predominantly via feces. Excretion occurs mainly via amide hydrolysis and as the unchanged drug.

Effects of Tablet Formulation, Food, or Gastric pH on the Bioavailability of Asundexian.

Absolute bioavailability (F) and the impact of gastric pH, tablet formulation, and food on the pharmacokinetics and safety of asundexian, an oral factor XIa inhibitor, was assessed in healthy White men aged 18-45 years in 4 studies. For F, fasted participants received 50 µg of [13 C7 ,15 N]-labeled asundexian intravenously 2 hours after 25 mg of asundexian orally. Tablet formulation (50-mg immediate release [IR], and different amorphous solid dispersion [ASD] IR 25-mg and 50-mg ASD IR tablets) and food effects were explored in 2 studies. Formulation was compared using 50-mg IR versus 25-mg ASD IR and 25-mg ASD IR versus 50-mg ASD IR (fasted); food effect using 25-mg ASD IR and 50-mg ASD IR. Gastric pH modulation was assessed using omeprazole or antacid coadministration with asundexian in the fasted state. Pharmacokinetic parameters included area under the concentration-time curve (AUC; and AUC/dose [D]) and maximum observed concentration (Cmax and Cmax /D) data were evaluable for 59 participants. F was 103.9%. Relative bioavailability with 25-mg ASD IR and 50-mg ASD IR tablets, respectively, was marginally affected by formulation (AUC/D ratios, 94.3% and 95.1%; Cmax /D ratios, 95.5% and 88.7%), food (AUC[/D] ratios, 91.1% and 96.9%; Cmax [/D] ratios: 78.3% and 95.1%), and gastric pH (omeprazole, no effect; antacid, AUC ratio, 89.9% and Cmax ratio, 83.7%). No serious adverse events or deaths occurred; most adverse events were mild or moderate. In summary, oral asundexian was well tolerated and demonstrated complete bioavailability irrespective of tablet formulation, food, or gastric pH.