Chemical formula: C₂₆H₂₄N₆O₂ Molecular mass: 452.196 g/mol PubChem compound: 11950170
Belumosudil is a selective Rho-associated, coiled-coil containing protein kinase-2 (ROCK2) inhibitor that mediates signalling in immune cellular function and fibrotic pathways.
At 2.2 times the maximum exposure of the approved recommended dose, belumosudil does not prolong the QT interval to any clinically relevant extent.
Median Tmax of belumosudil across studies was approximately 3 hours. Following a single oral dose of belumosudil 200 mg, mean absolute bioavailability (% coefficient of variation) was 64% (17%).
In healthy subjects, the administration of a single 200 mg dose of belumosudil with a high-fat and high-calorie meal (800 to 1 000 kilocalories with approximately 50% of total caloric content of the meal from fat) increased belumosudil Cmax to 2.25 times that following fasted administration and AUC to 2 times that following fasted administration. Median Tmax was delayed 0.5 hour.
Based on population PK modelling, the mean steady-state AUC (% coefficient of variation) in patients with cGVHD receiving 200 mg once daily administered with food was 18 800 (33%) h•ng/mL; mean steady-state Cmax was 2 230 (31%) ng/mL. With once daily administration, steady-state concentrations of belumosudil were achieved with an accumulation ratio of 1.2.
Based on population PK modelling, pharmacokinetics were described by a two compartmental model with a mean distribution half-life of 1.57 h (78%). Belumosudil mean (% coefficient of variation, CV) apparent volume of distribution of the central compartment was 35.8 L (93%). In in vitro preparations, binding to human serum albumin was 99.9% and binding to human α1-acid glycoprotein was 98.6%.
Based on in vitro assessment, CYP3A4 was the predominant CYP isoform responsible for the metabolism of belumosudil, although CYP2C8, CYP2D6 and UGT1A9 contributed to a lesser extent.
Population PK modelling results in cGVHD patients showed that belumosudil elimination mean (% coefficient of variation, CV) elimination half-life was 32.9 h (15%). Belumosudil mean (% CV) apparent clearance in patients (%CV) was 12.5 L/h (38%).
The Human Mass Balance study results indicated that faecal excretion is the major route of excretion (85% of the dose). Of the dose recovered in faeces, 30% was parent belumosudil. Less than 5% of the dose was recovered in urine.
Exposure to belumosudil (Cmax and AUC) appears to be slightly greater than dose proportional over the 20 to 500 mg once daily dose range, but less than dose-proportional for doses above 500 mg in healthy subjects. In subjects with cGVHD, the exposure increase between 200 and 400 mg is approximately proportional.
Based on population PK analysis no clinically relevant differences in belumosudil pharmacokinetics were observed with regard to age (20 to 77 years), race, gender, or weight (38.6 to 143 kg).
Based on population PK analysis, no clinically relevant differences in belumosudil pharmacokinetics were observed in patients with mild or moderate renal impairment. Severe renal impairment has not been studied.
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:
| Hepatic impairment category | Changes in belumosudil exposure in subjects with hepatic impairment compared to subjects with normal hepatic function | |||
| Total (Free + Bound) concentrations | Free concentrations | |||
|---|---|---|---|---|
| Cmax | AUC | Cmax | AUC | |
| Mild (Child-Pugh A) | 1.2-fold increase | 1.4-fold increase | 14% decrease | 19% decrease |
| Moderate (Child-Pugh B) | 6% decrease | 1.5-fold increase | 12% decrease | 1.4-fold increase |
| Severe (Child-Pugh C) | 1.3-fold increase | 4.2-fold increase | 5.4-fold increase | 16-fold increase |
No signs of PK dissimilarity were observed in three adolescent patients from whom sparse PK data were available.
In repeated dose studies, toxicity was observed at belumosudil average plasma concentration levels below or similar to the expected human exposure and in the studies of toxicity to reproduction, the toxicity was observed below the expected human exposure.
No evidence of special hazard for humans on safety pharmacology or genotoxicity was identified in vitro and in vivo studies.
In repeated oral dose studies in rats and dogs the adverse effects observed in one or both species included toxicities in the gastrointestinal tract (emesis, loose stools, and/or abnormal black contents, increase in salivation), liver (elevated liver enzymes, hypertrophy/increased organ weight, and cholestasis/inflammation), kidney (increased blood urea nitrogen, tubular changes, pigmentation, intracellular protein droplets in the epithelium), hemolymphoid system (regenerative anaemia, lymphocyte depletion in spleen and thymus), and reproductive system.
In male rats and dogs, toxicities included lower epididymis and testes weights associated with abnormal sperm findings such as multifocal bilateral spermatozoan degeneration in the epididymis and testes, and multinucleated spermatids in the testes, reduced motility and count of sperm; in the repeat dose studies the changes were reversible in dogs but not fully reversible in rats.
In female rats, lower uterine weights that correlated with uterine/cervical hypoplasia and decreased follicular development in ovaries related to adverse body weight reduction was observed. These changes were reversible.
Adverse effects in female rats (treated with belumosudil or untreated but mated with treated males) included increased pre- or post-implantation loss, decreased number of viable embryos and foetal malformations including absence of anus and tail, omphalocele, and dome shaped head.
In rabbits, maternal toxicity and embryo-foetal developmental effects (including spontaneous abortion, increased post-implantation loss, decreased percentage of live foetuses, and decreased foetal body weight and skeletal/external malformations) were observed.
No carcinogenic effects were reported in transgenic mice.
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