Quotient Sciences Predicting Belumosudil Drug-Drug Interactions Using a Physiologically Based Pharmacokinetic Model

Belumosudil is a selective inhibitor of Rho-associated protein kinase 2 (ROCK2) approved for treating chronic graft-versus-host disease (cGVHD) in adult and paediatric patients. In vitro incubations with human liver microsomes indicated that the metabolism of belumosudil involves various cytochrome P450 (CYP) isoforms: CYP3A4 responsible for 41.9% of belumosudil metabolism, with contributions from CYP2D6 (21.7%), CYP2C8 (14.2%), CYP1A2 (<5%), CYP2C19 (<5%) and uridine diphosphate glucuronosyltransferase (UGT)1A9 [1].

In a clinical study on drug-drug interactions (DDIs) [1], it was observed that the strong CYP3A4 inhibitor itraconazole (ITZ) led to a 25% increase in belumosudil exposure (AUC0-t), while the strong CYP3A4 and CYP2C8 inducer rifampicin (RIF) resulted in a 72% decrease in AUC0-t, compared to the exposure levels when belumosudil was administered alone.