Belumosudil Impacts Immunosuppression Pharmacokinetics in Patients with Chronic Graft-Versus-Host Disease

*EG/MP Co-first authors

Background: Belumosudil, a novel compound targeting the Rho-associated coiled-coil containing protein kinase 2 (ROCK2) was recently approved for the treatment of chronic graft-versus-host disease (cGVHD) in patients who failed at least two prior lines of systemic therapy (Cutler C, Blood 2021). Clinical evaluation of the pharmacokinetic (PK) effects of belumosudil (BEL) on other immunosuppressive therapies (IST) has not been performed. In vitro and pharmacokinetic modeling indicate BEL displays weak inhibition of CYP3A as well as inhibition of P-glycoprotein which are involved in the metabolism and excretion of several ISTs used concurrently for treatment of cGVHD such as tacrolimus (TAC), cyclosporine, and sirolimus (SIRO). Further evaluation of these potential interactions is crucial in optimizing initial immunosuppressive dosing with concurrent BEL use and to maintain therapeutic IST levels in cGVHD patients. The objective of this study was to determine the impact of BEL on plasma concentrations of tacrolimus and/or sirolimus in cGVHD patients.

Methods: We retrospectivity evaluated 30 patients between February 2019 and July 2022 at Moffitt Cancer Center who received BEL while concurrently on TAC and/or SIRO for the treatment of cGVHD. Patients were included if they had baseline IST plasma concentration before and at least one IST level during BEL therapy. Patients receiving TAC commonly had a target range of 3-7 ng/mL while those receiving SIRO mostly had a target range of 5-10 ng/ml. IST Concentration to dose (C/D) ratios were analyzed prior to initiation of BEL and at three time points after initiation.

Results: Median age was 63 years (range: 27-79); 86.7% received three or more lines of therapy and 60% had severe cGVHD per NIH consensus criteria (Jagasia MH, et al. Biol Blood Marrow Transplant. 2015). Over 50% of the patients had a Karnofsky Performance Status (KPS) less than 90% at time of BEL initiation. Additional baseline characteristics are described in Table 1. Patients taking SIRO (N = 26) or TAC (N = 12) concurrently with BEL had a statistically significant increase in mean C/D ratio between pre-BEL and all later C/D ratios while taking BEL (SIRO p<0.001, TAC p=0.014, Table 1). Upon co-administration of BEL, a higher proportion of patients on TAC and SIRO had supratherapeutic levels (25% TAC, 62% SIRO) at a median of 26 and 34.5 days, respectively (Figure 1). Most TAC levels became therapeutic after dose adjustments over evaluated time points (0%, 10% supratherapeutic), but SIRO levels were more likely to be supratherapeutic despite dose adjustment (33, 36% supratherapeutic) at later time points (Figure 1). The C/D ratio for both TAC and SIRO increased over the post-BEL assessment periods, with a significant difference between post-BEL 1 and 2 in the TAC group and a significant difference between post-BEL 1 and 3 in the SIRO group, indicating this drug interaction may require multiple dose adjustments (Figure 1). The increase in C/D ratio was significant in patients not taking a concurrent CYP3A inhibitor (N= 26, SIRO p<0.001, TAC p=0.001). The impact on the C/D ratio was less notable in patients taking a 3A4 inhibitor (N = 4) or BEL dosed daily combined with a proton pump inhibitor (N = 2), making it unclear if the potential effect of BEL is truly lessened in these patients or is reflective of small sample number. The interaction between multiple CYP3A interacting medications, such as concurrent TAC+SIRO+BEL (N = 8), is also unclear due to limited sample numbers. Eight patients discontinued BEL during the study period. After stopping BEL, 63% (N=5) required increased doses of TAC or SIRO and all 8 had a return of C/D ratios closer to pre-BEL.

Conclusions: In this single center study, we found that BEL impacts IST pharmacokinetics with clinical significance requiring dose adjustments. Notably, 12/26 patients on SIRO had a level of >15 ng/mL during the study period, indicating significant risk if this interaction is unmonitored. No patient on TAC had a level >15 ng/mL, but patients in this study had lower TAC goal ranges. Based on these findings, empiric dose reductions of at least 25% for SIRO and TAC should be considered with co-administration of BEL with close monitoring of IST levels at baseline and periodically during initial months of concurrent therapy. Future studies are needed to confirm BEL impact on IST pharmacokinetics, particularly in patients taking strong CYP3A4 inhibitors.

Faramand:Novartis: Research Funding; Kite/Gilead: Research Funding. Lazaryan:Sanofi: Consultancy; AvroBio: Consultancy; Humanigen: Consultancy; AmWel: Current equity holder in publicly-traded company; Teladoc: Current equity holder in publicly-traded company. Pidala:Johnson and Johnson: Research Funding; Takeda: Research Funding; Regeneron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclcis: Research Funding; BMS: Research Funding.

Tacrolimus and sirolimus kinetics are examined in this study used in chronic graft vs host disease