(M1530-02-10) Predicting Belumosudil Drug-Drug Interactions Using a Physiologically Based Pharmacokinetic Model

Purpose: Belumosudil is a selective inhibitor of Rho-associated protein kinase 2 (ROCK2) approved for treating chronic graft-versus-host disease (cGVHD) in adult and pediatric patients. In vitro incubations with human liver microsomes indicated that the metabolism of belumosudil involves various cytochrome P450 (CYP) isoforms with CYP3A4 responsible for 41.9% of belumosudil metabolism, with contributions from CYP2D6 (21.7%), CYP2C8 (14.2%), CYP1A2 ( < 5%), CYP2C19 ( < 5%) and uridine diphosphate glucuronosyltransferase (UGT)1A9 [1]. In a clinical drug-drug interaction (DDI) study [1], it was observed that a strong CYP3A4 inhibitor, itraconazole (ITZ) led to a 25% increase in belumosudil exposure (AUC0-t), while a strong CYP3A4 and CYP2C8 inducer, rifampicin (RIF) resulted in a 72% reduction in AUC0-t. This study aims to use previously published belumosudil data to develop a Physiologically Based Pharmacokinetic (PBPK) model that predicts the clinically observed DDI of ITZ and RIF on belumosudil pharmacokinetics. Additionally, it aims to use the model to evaluate the impact of efavirenz (EFV), a moderate CYP3A4 inducer, on belumosudil exposures.

Methods: A whole-body PBPK model for belumosudil was developed in GastroPlus™ v9.7 (SimulationsPlus, Inc.). The ACAT™ model was used to describe the intestinal dissolution, precipitation, and absorption of belumosudil. The model incorporates physicochemical parameters predicted from structure using ADMET Predictor™ (v9.5) along with published solubility and in-vitro metabolism data [1]. Permeability and clearance terms were fitted using PK data from two separate clinical studies that evaluated PK following intravenous (IV) microtracer infusion (100 μg) and oral (200 mg immediate release tablet, with and without food) dosing in healthy male subjects [1,2]. The model was then used to predict DDIs with ITR and RIF, using default perpetrator models from the GastroPlus™ DDI database (version 9.7) and matching dosing regimens to the clinical study design [1]. Subsequently, the model was evaluated in predicting DDIs with EFV.

Results: The PBPK model accurately predicted belumosudil exposures with percent prediction errors (%PE) of 15% and 10% for Cmax and AUC0-t, respectively, following IV infusion. For oral administration in the fasted state, %PEs were 1% and 17% for Cmax and AUC0-t, respectively. The food effect ratio was also well-predicted with %PEs of -23% and 9% for Cmax and AUC0-t, respectively. The model accurately predicts the increase in exposure resulting from co-administration of ITZ; predicted DDI ratio; Cmax 1.12, AUC0-t 1.25, observed DDI ratio; Cmax: 1.2 (1.11-1.31), AUC0-t 1.25 (1.17-1.33). Moreover, the greater (likely to be clinically relevant) negative interaction observed following RIF dosing was also predicted by the model; predicted DDI ratio; Cmax 0.4, AUC0-t: 0.26, observed DDI ratio; Cmax 0.41 (0.37-0.44), AUC0-t 0.28 (0.26-0.30). The interaction with EFV was predicted with DDI ratios of 0.76 for Cmax and 0.56 for AUC0-t, indicating a moderate interaction.

Conclusion: The developed PBPK model successfully predicted the clinical DDIs of belumosudil with ITZ and RIF and provided reasonable estimates for interaction with EFV in healthy male subjects. This model serves as a robust tool for predicting belumosudil interactions with other potential perpetrator drugs, supporting its further application in clinical DDI risk assessment.

References: [1] Schueller O, Willson A, Singh N, Lohmer L, Alabanza A, Patel J. A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered with CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors. Clin Pharmacol Drug Dev. 2022 Jul;11(7):795-806. doi: 10.1002/cpdd.1082. Epub 2022 Mar 1. PMID: 35230741.
[2] Schueller O, Skucas E, Regev G, Shaw I, Singh N, Sanghvi M, Croft M, Lohmer L, Alabanza A, Patel J. Absolute Bioavailability, Mass Balance, and Metabolic Profiling Assessment of [14 C]-Belumosudil in Healthy Men: A Phase 1, Open-Label, 2-Part Study. Clin Pharmacol Drug Dev. 2022 Jul;11(7):786-794. doi: 10.1002/cpdd.1085. Epub 2022 Mar 1. PMID: 35231159.

Belumosudil simulations with and without DDIs