Belumosudil Significantly Affects IST Serum Concentrations

Recently, the novel Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor, belumosudil, was approved for the treatment of chronic graft-versus-host disease (GVHD) in patients who failed at least 2 prior lines of therapy. However, the effects of belumosudil on the pharmacokinetics of other immunosuppressive therapies (ISTs) are unknown, according to a presentation at the 64th ASH Annual Meeting and Exposition.

Researchers, led by Eric Gaskill, examined plasma concentrations of tacrolimus or sirolimus in patients with chronic GVHD who received belumosudil and determined it had a clinically significant impact on IST pharmacokinetics, requiring dose adjustments.

Belumosudil Impacts Tacrolimus or Sirolimus Concentration

The study retrospectively enrolled 30 patients with chronic GVHD who received belumosudil concurrently with tacrolimus (n=12) or sirolimus (n=26) at the Moffitt Cancer Center between February 2019 and July 2022. Authors noted tacrolimus and sirolimus typically had target concentration ranges of 3-7 ng/mL and 5-10 ng/mL, respectively. Concentration to dose (C-D) ratios were measured at baseline and at 3 points during treatment.

Of note, patients on sirolimus (P<.001) or tacrolimus (P=.014) who initiated belumosudil had significant increases in mean C-D ratio from baseline to all points during concurrent belumosudil treatment. In addition, a higher proportion of patients on concurrent belumosudil had supratherapeutic levels (tacrolimus, 25%; sirolimus, 62%). Researchers found most tacrolimus levels returned to therapeutic ranges after dose adjustments; however, sirolimus levels were more likely to remain at supratherapeutic levels even after dose adjustments.

Due to the different tacrolimus and sirolimus C-D ratios at each point during belumosudil treatment, the authors suggested this combination may require multiple dose adjustments. They also determined a “significant risk” if this drug interaction is left unsupervised, as 12 of the 26 sirolimus patients had sirolimus concentrations >15 ng/mL.

Ultimately, the authors proposed that “empiric dose reductions of at least 25% for [sirolimus] and [tacrolimus] should be considered with co-administration of [belumosudil], with close monitoring of IST levels at baseline and periodically during initial months of concurrent therapy.”

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