Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects

Abstract

Belumosudil is a selective Rho‐associated coiled‐coil containing protein kinase 2 inhibitor. A capsule formulation was used during early clinical development of belumosudil; it was later replaced by a tablet formulation, which mimicked the capsule's release properties and facilitated manufacturing scalability. To assess belumosudil's pharmacokinetics, including potential food effects, and evaluate the relative bioavailability of the 2 formulations, 2 phase 1 clinical trials were conducted. Administration of both belumosudil tablets and capsules with food increased exposure ≈2× as compared to the fasted state and delayed time to maximum concentration by 0.5 hour, indicating a decrease in the rate but increase in the extent of absorption with fed administration. Relative bioavailability was slightly higher when belumosudil was administered as tablets vs capsules, although the difference was not clinically meaningful. Safety and tolerability were generally consistent with the known safety profile of belumosudil. The results of these studies support administration of belumosudil with food.

A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors

“…The effect of CYP3A4 induction on belumosudil metabolism is further supported by in vitro assessments, which determined that the metabolism of belumosudil to KD025m1 was CYP3A4 and CYP2C8 dependent, while metabolism to KD025m2 was CYP3A4 dependent, with further metabolism modulated by UGT1A1 (unpublished work). As rifampicin is known to induce CYP3A4, CYP2C8, and UGT1A1, 17–20 the observed increase in KD025m1 exposure with rifampicin coadministration is consistent with the proposed metabolic pathway of belumosudil 9 . Additionally, whereas production of KD025m1 may increase from induction of both CYP3A4 and CYP2C8, induction of the UGT1A1 enzyme may increase the elimination rate of KD025m2 even if production via CYP3A4 is increased, thus explaining the decrease in exposure of KD025m2 with rifampicin administration.…”

“…As rifampicin is known to induce CYP3A4, CYP2C8, and UGT1A1, [17][18][19][20] the observed increase in KD025m1 exposure with rifampicin coadministration is consistent with the proposed metabolic pathway of belumosudil. 9 Additionally, whereas production of KD025m1 may increase from induction of both CYP3A4 and CYP2C8, induction of the UGT1A1 enzyme may increase the elimination rate of KD025m2 even if production via CYP3A4 is increased, thus explaining the decrease in exposure of KD025m2 with rifampicin administration.…”

“…Before receiving belumosudil, a standard breakfast was provided, consisting of 1 bowl of cereal, 200 mL of semi‐skimmed milk, and 1 croissant or roll with prepackaged jam. All belumosudil doses were administered 30 minutes after the start of the meal; as belumosudil has a known food effect, 9 it is recommended to be administered with food.…”

“…Sample size calculations were based on the following assumptions: (1) intrasubject variability of 50% for C max and 40% for AUC from time 0 to the last quantifiable concentration (AUC last ), based on a previous food effect study 9 ; (2) 90%CI for C max and AUC last with type 1 error of 0.05; (3) acceptance interval of 70.00% to 143.00%; and (4) 80% powder, assuming the true ratio is between 95.00 and 105.00. Based on these assumptions, it was estimated that 34 subjects evaluable for C max , the PK parameter with the highest variability, were needed.…”

A Phase 1 Thorough QT/QTc Study of Therapeutic and Supratherapeutic Doses of Belumosudil in Healthy Subjects

“…Administration of belumosudil in the fed state increases exposure ≈2× compared to the fasted state and delays time to maximum concentration by ≈0.5 hours. 8 Preclinical investigations indicated that belumosudil undergoes hepatic metabolism to form two main metabolites: KD025m1 (a ROCK2 active minor metabolite, inhibition constant [Ki] = 55 nM) and KD025m2 (a ROCK2 inactive major metabolite [Ki] = 338 nM). Clinical exposure (AUC and C max ) for both metabolites is approximately ≤20% of belumosudil exposure.…”