Introduction: Belumosudil is a Rho-associated coiled-coiled (ROCK) 2 inhibitor that is approved for the treatment of chronic graft-versus-host-disease (cGVHD) by the US Food and Drug Administration in 2021. Pharmacokinetic studies on belumosudil have shown that it exhibits weak inhibition of CYP3A4, 1A2, 2C19, 2D6, and UDP-glucuronosyltransferase 1A1/9, and may have transporter-mediated effects on BCRP, OATP1B1, and p-glycoprotein (p-gp) [Blair; Drugs 2021]. As a result, belumosudil may interact with immunosuppressants (IS/S) with a narrow therapeutic index such as tacrolimus (TAC) and sirolimus (SIRO), commonly used in the prevention and treatment of GVHD. Both drugs are substrates of CYP3A4 and p-gp, which could potentially lead to drug-drug interaction and supratherapeutic drug levels resulting in increased toxicity from Tac/Siro such as thrombotic microangiopathy (TMA), acute kidney injury (AKI), and neurotoxicity. A recent study demonstrated that belumosudil increased TAC and SIRO concentration/dose ratios (C/D ratio) by 113% and 160% respectively, thus empiric dose reductions of 25-50% were recommended by the authors [Gonzalez et al.; Transplant Cell Ther. 2023]. We sought to analyze the impact of belumosudil on therapeutic drug monitoring (TDM) of patients who were on either tacrolimus or sirolimus at our center to confirm these findings.

Methods: We retrospectively reviewed medical records of 68 patients who received belumosudil for treatment of cGVHD and were already taking either TAC or SIRO. Patients were required to have one IS/S level available within 35 days of initiating belumosudil to be included for analysis. If more than one level was available, the first level had to be within 14 days of starting and the second level must be collected between 14-35 days of starting. Secondary outcomes included the incidence of supratherapeutic IS/S and organ toxicity while on belumosudil and IS/S.

Results: The median age of patients was 56 years (range 19-79) with a predominantly male (55.9%) and mostly Caucasian or Hispanic background (51.5% and 35.3% respectively). Patients were on belumosudil for a median of 10.8 months (range 0.23-74.3). In this cohort, 70.6% (48/68) were on TAC, 57.4% (39/68) were on SIRO, and 27.9% (19/68) were on both. Azoles were used concomitantly in 51.5% of patients (35/68), with 65.7% (23/35) on posaconazole, 31.4% (11/35) on isavuconazole, and 2.9% (1/35) on voriconazole. Four patients started an azole after starting belumosudil (2 on posaconazole, 1 on fluconazole, and 1 on isavuconazole). Prior to starting belumosudil, 64% (37/58) had stable baseline IS/S levels (unstable was defined as TAC/SIRO levels within preceding 8 weeks of starting belumosudil being more than twice the baseline IS/S level or a level that was supratherapeutic). Median baseline level for TAC was 4.1 ng/mL (range 2-9.7) and SIRO 5.7 ng/mL (range 2-14.5). After starting belumosudil, the median time to Level 1 and Level 2 were 7 days (range 0-12) and 16 days (range 11-34) respectively. The median Level 1 for TAC was 6.0 ng/mL (range 2-17.8) and SIRO was 6.55 (range 2-23.5), requiring dose adjustments in 12.5% (6/48) and 15.4% (6/39). Median Level 2 for TAC was 5.5 ng/mL (range 2-18.8) and SIRO 7.4 ng/mL (range 2-54.6), requiring dose adjustment in 18.7% (9/48) and 10.3% (4/39). TAC levels increased a median +25.8% (range -37-336) from baseline to Level 1 and +37.4% (range -74-500) from Level 1 to 2, while SIRO levels changed by -8.9% (range -43-1075) and +25% (range -65-950) during a similar timeframe. Severe toxicities were rarely seen (13.2%; 9/68) and only with TAC. There were 7 cases of AKI (4 patients were on both TAC/SIRO), 1 case each of tremors and TMA. Supratherapeutic levels (>10 ng/mL) occurred with TAC 20% (6/20) and SIRO 30.4% (7/23) for Level 1 and 25% for both groups for Level 2 (11/44 and 9/36 respectively).Conclusions: Our study confirms the drug interaction between TAC/SIRO, with the increase in TAC/SIRO levels more pronounced with the second level after starting belumosudil. However, severe toxicities were rarely seen. Based on our data, we recommend close TDM of TAC and SIRO, but no dose adjustment is warranted when belumosudil is added.

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2025
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