Pharmacokinetics of Belumosudil and Its Metabolites in Individuals With Hepatic Impairment

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.