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Pharmacokinetics of Belumosudil and Its Metabolites in Individuals With Hepatic Impairment

Year: 2025

Type: article

Abstract: ABSTRACT Belumosudil, an orally administered Rho‐associated coiled‐coil–containing protein kinase 2 selective inhibitor drug for treatment of chronic graft‐versus‐host disease (GVHD), is predominantly eliminated via the liver. This phase 1, open‐label, non‐randomized, parallel‐group study (NCT04166942) evaluated belumosudil pharmacokinetics and safety after a single 200‐mg dose in participants with mild, moderate, or severe hepatic impairment (Child‐Pugh classification), matched with healthy participants with normal hepatic function. M1 and M2 metabolites were also assessed. Geometric least squares mean (GLSM) ratios (90% confidence intervals [CI]) for belumosudil area under the plasma concentration‐time curve (AUC) from time 0 to the time to infinity (AUC 0‐∞ ), AUC to the time of last measurable concentration (AUC 0− t ), and maximum concentration ( C max ) were 1.36 (0.83–2.21), 1.48 (0.96–2.28), and 1.20 (0.91–1.58), respectively, for the mild impairment group, and 1.51 (0.98–2.33), 1.50 (0.97–2.31), and 0.94 (0.60–1.48), respectively, for the moderate impairment group. Severe hepatic impairment markedly increased belumosudil AUC 0–∞ and AUC 0– t but had no apparent effect on C max ; GLSM ratios (90% CI) were 4.21 (2.20–8.06), 3.23 (1.53–6.81), and 1.32 (0.90–1.96), respectively. A post hoc analysis was conducted using the National Cancer Institute‐Organ Dysfunction Working Group (NCI‐ODWG) classification for hepatic impairment. Assessment by NCI‐ODWG criteria, compared with Child‐Pugh criteria, revealed a higher range of exposure in participants with moderate hepatic impairment. Belumosudil can be taken by patients with mild hepatic impairment without dose adjustment; avoid use in patients with moderate hepatic impairment (Child‐Pugh B) or severe hepatic impairment (Child‐Pugh C) without liver GVHD.

Source: Clinical and Translational Science

DOI: 10.1111/cts.70265