Researchers at the Moffitt Cancer Center evaluated the pharmacokinetic effects of Belumosudil (BEL), a recently approved drug for treatment of chronic graft-versus-host disease (cGVHD) on two immunosuppressive (IS) agents tacrolimus and sirolimus. This clinical investigation was prompted by evidence from in vitro data indicating that BEL may have possible interactions with drugs with a narrow therapeutic index used to treat cGVHD through cytochrome P450 (CYP3A4) and p-glycoprotein interactions.
Approximately 50% of allogeneic hematopoietic cell transplantation (alloHCT) recipients who develop cGVHD fail initial corticosteroid therapy with or without calcineurin inhibitors. Current approaches in steroid-refractory patients rely on multiple factors, including the use of concomitant IS agents as a second-line therapy. BEL is a novel oral Rho-associate coiled-coil kinase (ROCK) 2 inhibitor recently approved for treating cGVHD in patients who have failed two or more prior lines of systemic therapy. BEL can decrease T helper 17 and T follicular helper cells through regulating STAT pathway, allowing for successful modulation of the immune system to reduce effector T cell signaling and restore immunologic tolerance.
This retrospective single-center study involved 37 patients meeting eligibility criteria who had IS levels measured at baseline prior to starting BEL and at least one subsequent IS measurement to assess changes over time were included in the analysis. The primary endpoint was the concentration-dose (C/D) ratio of sirolimus and tacrolimus before and after concurrent administration of BEL. The C/D ratio was assessed initially before initiation of BEL (pre-BEL) and then at up to three subsequent time points after initiation of BEL (post-BEL 1, 2, and 3).
The authors found that concomitant administration of BEL with both tacrolimus and sirolimus produced a significant interaction necessitating close monitoring and IS dosage adjustments. Patients receiving both tacrolimus (n = 16) and sirolimus (n = 30) concurrently with BEL had statistically significant increases in C/D ratios between pre-BEL and all post-BEL therapeutic drug monitoring assessments. Patients receiving sirolimus in addition to BEL required a mean dosage reduction of 38% from the pre-BEL to final post-BEL assessments. The continued rise in C/D ratio at later assessment points indicated a potential need for multiple sirolimus dosage adjustments to maintain the therapeutic range and showed that these adjustments take a significant time to reach steady state after addition of BEL. Patients exposed to sirolimus in addition to BEL were more likely to have elevated IS levels, and most patients in the study who experienced edema also had at least 1 sirolimus level >15 ng/mL, raising a concern that this interaction may promote adverse event without dosage adjustment. The authors conclude that BEL impacts tacrolimus and sirolimus pharmacokinetics with clinical significance, resulting in necessary dose adjustments for the IS agents with concomitant use. Given the significant risk of this interaction resulting in supratherapeutic levels, they recommend initiation of empiric dose adjustments of at least 25% with close IS monitoring at baseline and periodically during the initial months of concurrent therapy.
Gonzalez R, Gaskill E, Padilla M, et al. Belumosudil Impacts Immunosuppression Pharmacokinetics in Patients with Chronic Graft-versus-Host Disease. Transplant Cell Ther.
2023; S2666-6367(23)01359-3. https://doi: 10.1016/j.jtct.2023.06.011.
Tags: study, GVHD, cGVHD, chronic GVHD, graft-versus-host disease, T cells, graft-versus-host