Variability in belumosudil exposure due to coadministration of voriconazole and isavuconazole in a patient with chronic graft-versus-host disease: Case report

OBJECTIVE: To characterize intra-patient variability in belumosudil exposure during coadministration of two azole antifungals that differ in cytochrome P450 3A4 (CYP3A4) inhibition strength - voriconazole (strong) vs. isavuconazole (moderate) - in a patient with steroid-refractory chronic graft-versus-host disease (cGVHD), and to discuss the subsequent implications for therapeutic drug monitoring (TDM). CASE HISTORY: A man in his 50s with pulmonary cGVHD was initiated on belumosudil 200 mg once daily after cord blood transplantation, which was later increased to 200 mg twice daily (400 mg/day). Concomitant voriconazole was switched to isavuconazole due to elevated galactomannan levels and Common terminology criteria for adverse events (CTCAE) grade 2 hepatotoxicity. A single plasma sample was collected at 2 hours post-dose (C2) to approximate the peak exposure, based on a reported median time to maximum concentration of ~ 2 hours in healthy Japanese adults. RESULTS: Over the clinical course, 28 C2 samples were analyzed (18 with voriconazole and 10 with isavuconazole). The overall median C2 was 857.04 ng/mL (range, 173.59 - 2,749.19). The median C2 was significantly higher with voriconazole (889.88 ng/mL) than with isavuconazole (395.96 ng/mL) according to the exact Wilcoxon signed-rank test (p < 0.001). Median plasma concentrations of coadministered azoles were 1.94 µg/mL (voriconazole) and 7.04 µg/mL (isavuconazole). CONCLUSION: Belumosudil exposure varied according to the degree of CYP3A4 inhibition (voriconazole > isavuconazole). These intra-patient data, together with clinical factors affecting absorption and hepatic function, support consideration of TDM and careful antifungal selection when combining belumosudil with azoles, particularly in pulmonary cGVHD where treatment responses are often limited.