Belumosudil

Belumosudil exposure-response relationships and the time course of pharmacodynamic response are not established.

Cardiac electrophysiology

At 2.4 times the maximum exposure for approved recommended dose, belumosudil does not prolong the QT interval to any clinically relevant extent.

The following pharmacokinetic parameters are presented for chronic GVHD patients administered belumosudil 200 mg once daily, unless otherwise specified. The mean (% coefficient of variation, CV) steady-state AUC and C_max of belumosudil was 22,700 (48) h∙ng/mL and 2390 (44%) ng/mL, respectively. Belumosudil C_max and AUC increased in an approximately proportional manner over a dosage range of 200 and 400 mg (1 to 2 times once daily recommended dosage). The accumulation ratio of belumosudil was 1.4.

Absorption

Median T_max of belumosudil at steady state was 1.26 to 2.53 hours following administration of 200 mg once daily or twice daily in patients. The mean (CV) bioavailability was 64 (17%) following a single belumosudil dose in healthy subjects.

Effect of food

Belumosudil C_max and AUC increased 2.2 times and 2 times, respectively, following administration of a single belumosudil dose with a high-fat and high-calorie meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) compared to the fasted state in healthy subjects. Median T_max was delayed 0.5 hours.

Distribution

The geometric mean volume of distribution after a single dose of belumosudil in healthy subjects was 184 L (geo CV% 67.7%).

Belumosudil binding to human serum albumin and human α₁-acid glycoprotein was 99.9% and 98.6%, respectively, in vitro.

Elimination

The mean (CV) elimination half-life of belumosudil was 19 hours (39), and clearance was 9.83 L/hours (46%) in patients.

Metabolism

Belumosudil is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9, in vitro.

Excretion

Following a single oral dose of radiolabeled belumosudil in healthy subjects, 85% of radioactivity was recovered in feces (30% as unchanged) and less than 5% in urine.

Specific populations

No clinically significant differences in belumosudil pharmacokinetics were observed with regard to age (18 to 77 years), sex, weight (38.6 to 143 kg), or mild to moderate renal impairment (eGFR ≥60 and <90 mL/min/1.72m² to eGFR ≥30 and <60 mL/min/1.72m²). The effect of severe renal impairment on the pharmacokinetics of belumosudil has not been studied.

Patients with hepatic impairment

Following a single 200 mg dose of belumosudil, changes in belumosudil exposure in subjects with varying degrees of hepatic impairment based on Child-Pugh score without liver GVHD relative to subjects with normal hepatic function is shown in the following table.

Effect of varying degrees of hepatic impairment on belumosudil exposure:

Drug interaction studies

Clinical studies and model-informed approaches

Effects of other drugs on belumosudil:

Strong cytochrome P450 (CYP) 3A inhibitors: There was no clinically meaningful effect on belumosudil exposure when coadministered with itraconazole in healthy subjects.

Strong CYP3A inducers: Coadministration of rifampin decreased belumosudil C_max by 59% and AUC by 72% in healthy subjects.

Moderate CYP3A inducers: Coadministration of efavirenz is predicted to decrease belumosudil C_max by 19% and AUC by 35% in healthy subjects.

Proton pump inhibitors: Coadministration of rabeprazole decreased belumosudil C_max by 87% and AUC by 80%, and omeprazole decreased belumosudil C_max by 68% and AUC by 47% in healthy subjects.

Effects of belumosudil on other drugs:

CYP3A substrates: Coadministration of belumosudil is predicted to increase midazolam (a sensitive CYP3A substrate) C_max and AUC approximately 1.3- and 1.5-fold, respectively.

CYP2C9 substrates: Coadministration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C9 substrates (such as warfarin).

CYP2C8 substrates: Coadministration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C8 substrates that are not an OATP1B1 substrate.

In vitro studies:

Transporter systems: Belumosudil is a substrate of P-gp. Belumosudil inhibits BCRP, P-gp, and OATP1B1 at clinically relevant concentrations.

Enzymes systems: Belumosudil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1 and UGT1A9.