Key result
Single doses of asundexian 25 mg were well tolerated, and age, sex, chronic kidney disease, and liver disease had no clinically meaningful effect on asundexian exposure.
Why the study?
Asundexian is under investigation for secondary stroke prevention in at-risk patients who often have advanced age, impaired organ function, and comorbidities, requiring evaluation of these intrinsic factors on its pharmacology.
Does age, sex, renal impairment, or hepatic impairment affect the safety, pharmacokinetics, and pharmacodynamics of a single 25 mg dose of asundexian?
Does age, sex, renal impairment, or hepatic impairment affect the safety, pharmacokinetics, and pharmacodynamics of a single 25 mg dose of asundexian?
Age, sex, mild-to-severe renal impairment, and mild-to-moderate hepatic impairment do not have a clinically meaningful effect on the pharmacokinetics or safety of asundexian 25 mg, supporting its use without dose adjustment in these populations.
No dose adjustment needed for asundexian by age, sex, or organ function; leaves open dedicated efficacy/safety trials in these populations.
Asundexian is a reversible and selective inhibitor of activated factor XI. It is currently under investigation for the prevention of secondary stroke in at-risk patients; these patients are often characterised by advanced age, impaired organ function and comorbidities. This article summarises results from three Phase I studies that investigated the effects of age and sex (study 1), chronic kidney disease including end-stage kidney disease (ESKD) on dialysis and dialysis-free days (study 2) and Child–Pugh A and B liver disease (study 3) on the safety, pharmacokinetics and pharmacodynamics of a single oral dose of asundexian 25 mg. Study 1 was a multicentre, randomised, single-blind, placebo-controlled group-stratification design; study 2 was a single-centre, non-randomised, non-placebo-controlled, non-blinded group-stratification design; and study 3 had a non-randomised, non-blinded, non–placebo-controlled group-stratification design. Single doses of asundexian 25 mg were generally well tolerated in all three studies, with no asundexian-related bleeding events or treatment-emergent adverse events of special interest. Point estimates (geometric least squares [LS] means) (90% confidence intervals [CIs]) for the total asundexian area under the plasma concentration–time curve (AUC) for participants aged ≥ 65 to < 75 years versus ≥ 18 to < 45 years and ≥ 75 to ≤ 80 years versus ≥ 18 to < 45 years were 1.257 (1.134–1.393) and 1.288 (1.158–1.433), respectively, and for females versus males, it was 1.084 (0.995–1.182). Point estimates (geometric LS means) (90% CIs) for unbound AUC in participants in estimated glomerular filtration rate (eGFR) categories G2 (60–89 mL/min/1.73 m2), G3 (30–59 mL/min/1.73 m2) and G4 (15–29 mL/min/1.73 m2) versus control were 1.003 (0.698–1.443), 0.791 (0.550–1.138) and 0.882 (0.606–1.285), respectively, and in participants with ESKD on dialysis-free day versus control was 0.597 (0.406–0.877). There was no effect of the dialysis procedure on the pharmacokinetics of asundexian. In participants deemed Child–Pugh class A and Child–Pugh class B, geometric LS means (90% CIs) for unbound AUC were 0.834 (0.597–1.164) and 1.143 (0.810–1.612), respectively, when compared to participants with normal liver function. Activated partial thromboplastin time (aPTT) was assessed as a pharmacodynamic variable of interest. Geometric mean maximum aPTT prolongation as a ratio to baseline after administration of asundexian 25 mg ranged from 1.45 to 1.55 in all age and sex groups, 1.49–1.59 in the control and eGFR G2 to G4 groups, 1.38–1.54 in the control and ESKD groups on dialysis and dialysis-free day and 1.38–1.89 in the healthy control and liver impairment groups. The effects of the investigated intrinsic factors on the exposure of asundexian were small and not considered clinically relevant. The impact of lower exposure in participants with ESKD requires further investigation. Pharmacodynamics were as expected. EudraCT 2022-000196-38 and 2020-000626-25. Asundexian is a drug being developed for the prevention of secondary stroke (another stroke in people who have already had a stroke caused by a partial or complete obstruction of brain blood flow) in people who are at risk and is currently under investigation in the OCEANIC-STROKE trial. Many of these patients at risk are elderly and experience a decline in how well their organs work, along with other health conditions. Asundexian is most abundant in the blood stream in its unchanged form (without being broken up by the liver). Asundexian is removed from the body mainly by the liver and partly by the kidney. This article summarises results from three Phase I studies which looked at the effects of age and sex (study 1); chronic kidney disease, including end-stage kidney disease on haemodialysis (a procedure that helps with cleaning the blood and removing waste from the body; study 2); and liver impairment (study 3) on how asundexian is processed and its effects on the body. Overall, single tablets of asundexian 25 mg were well tolerated. The effects of age, sex, kidney function and liver function on the amount of asundexian in the body were small and not considered clinically relevant.
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Brase et al. (2024) studied Healthy volunteers and participants with renal or hepatic impairment (n=131). Asundexian vs. Placebo or matched healthy controls was evaluated on Total asundexian area under the plasma concentration-time curve (AUC) ratio (age ≥65 to <75 years vs ≥18 to <45 years) (Ratio of geometric LS means 1.257, 95% CI 1.134-1.393). Single doses of asundexian 25 mg were well tolerated, and age, sex, chronic kidney disease, and liver disease had no clinically meaningful effect on asundexian exposure.
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