In Vitro and Clinical Evaluations of UGT1A1‐, P‐gp‐, OATP1B1‐, and BCRP‐Mediated Drug–Drug Interactions of Belumosudil, a Potent ROCK2 Inhibitor

Belumosudil is an oral selective rho-associated coiled-coil containing protein kinase 2 inhibitor, approved as a treatment for chronic graft-versus-host disease. Prior clinical studies demonstrated that coadministration with strong CYP3A4 inducers or proton pump inhibitors requires dose modification of belumosudil. In vitro assessments suggested that belumosudil may inhibit uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), P-glycoprotein (P-gp), organic anion transporting polypeptide 1B1 (OATP1B1), and breast cancer resistance protein (BCRP), resulting in drug-drug interactions (DDIs). This three-part clinical DDI study (NCT05806567) was conducted to assess the effect of multiple doses of belumosudil (200 mg daily) on the single-dose pharmacokinetics of raltegravir (UGT1A1-sensitive substrate), dabigatran etexilate (P-gp-sensitive substrate), and rosuvastatin calcium (OATP1B1/BCRP-sensitive substrate). Although there was no marked change in raltegravir exposure after coadministration with belumosudil, exposure to the glucuronide metabolite was decreased by 39.6% (area under the curve from time 0 to the time of last measurable concentration [AUC_0-last]) and 42.4% (maximum observed concentration [C_max]), suggesting that belumosudil is an in vivo inhibitor of UGT1A1. There was an approximate 2-fold increase in C_max, AUC_0-last, and AUC from time 0 extrapolated to infinity (AUC_0-inf) for dabigatran etexilate, suggesting a potential and clinically relevant DDI for belumosudil and sensitive P-gp substrates. C_max and AUC_0-last for rosuvastatin calcium increased by 3.6-fold and 4.6-fold, respectively, suggesting a clinically relevant interaction with drugs that are substrates of OATP1B1 or BCRP. There was no impact of coadministration with raltegravir, dabigatran etexilate, or rosuvastatin calcium on belumosudil pharmacokinetics, and belumosudil was well tolerated.