A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors

Abstract

Belumosudil is a selective Rho-associated protein kinase 2 inhibitor. Inhibition of Rho-associated protein kinase 2 has emerged as a promising treatment for chronic graft-versus-host disease by restoring immune homeostasis and reducing fibrosis. In vitro assessments have suggested that metabolism of belumosudil is primarily dependent on cytochrome P450 (CYP) 3A4 activity and that the solubility of belumosudil is pH dependent. As such, this 2-part clinical drug-drug interaction study was conducted to assess the effect of itraconazole (a strong CYP3A4 inhibitor), rifampicin (a strong CYP3A4 inducer), rabeprazole, and omeprazole (both proton pump inhibitors) on the pharmacokinetics of belumosudil. No clinically relevant change in belumosudil exposure was observed following a 200-mg single oral dose of belumosudil with itraconazole; however, exposure of main metabolite, KD025m2, was decreased. Consistent with the proposed metabolic pathway of belumosudil, the strong CYP3A4 inducer rifampicin significantly decreased exposure of belumosudil and KD025m2 and increased KD025m1 exposure. When a 200-mg single oral dose of belumosudil was coadministered with both rabeprazole and omeprazole, parent and metabolite exposures were largely reduced, suggesting that belumosudil dosage should be increased when given with PPIs. Administration of belumosudil with and without perpetrator drugs was safe, and no notable adverse events were reported.

Two‐Part Phase 1 Study to Evaluate the Taste Profile of Novel Belumosudil Oral Suspensions and Assess the Relative Bioavailability and Food Effect of the Selected Belumosudil Oral Suspension Compared With Oral Tablet Reference in Healthy Male Participants

“…These AEs all occurred within 1 hour of t max of belumosudil and are consistent with AEs reported in previous belumosudil clinical studies. [11][12][13]18 No other AEs were considered related to belumosudil, and all AEs resolved prior to the end of the study.…”

“…Overall, the safety and tolerability of the belumosudil tablet and oral suspension were in line with previous results for the tablet formulation. 12,13,18…”

A Phase 1 Thorough QT/QTc Study of Therapeutic and Supratherapeutic Doses of Belumosudil in Healthy Subjects

“…A clinical drug-drug interaction study, however, did not demonstrate a meaningful impact of itraconazole (a CYP3A4 inhibitor) on belumosudil PK. 10 Mild and moderate renal impairment did not impact belumosudil exposure, mild and moderate hepatic impairment did not notably increase belumosudil exposure, and evaluation in subjects with severe hepatic impairment has not been completed. 7 Belumosudil at the studied doses did not have a clinically relevant effect on HR or the PR and QRS inter-vals.…”

“…The main factors that may potentially increase the clinical exposure of belumosudil, particularly C max (the exposure parameter of significance for evaluating drug‐induced QTc prolongation), are concomitant administration with a CYP3A4 inhibitor (the main belumosudil metabolizing enzyme in vitro) and organ impairment. A clinical drug–drug interaction study, however, did not demonstrate a meaningful impact of itraconazole (a CYP3A4 inhibitor) on belumosudil PK 10 . Mild and moderate renal impairment did not impact belumosudil exposure, mild and moderate hepatic impairment did not notably increase belumosudil exposure, and evaluation in subjects with severe hepatic impairment has not been completed 7 …”

“…9 A clinical drug-drug interaction study with itraconazole (a strong CYP3A4 inhibitor) and rifampicin (a strong CYP3A4 inducer) supports the role of CYP3A4 in belumosudil metabolism. 10 While no meaningful change in belumosudil exposure was noted for administration with itraconazole, a decrease in exposure of KD025m2 and KD025m1 was observed. Coadministration with rifampicin resulted in a significant decrease in belumosudil exposure and an increase in KD025m1 exposure.…”