Year: 2025
Type: article
Abstract: Aim Small‐molecule activin receptor‐like kinase‐2 inhibitor zilurgisertib (INCB000928) is under investigation in a pivotal trial for the treatment of fibrodysplasia ossificans progressiva (FOP), an ultrarare genetic condition. This analysis assessed effects of renal and hepatic impairment on zilurgisertib pharmacokinetics. Methods Two open‐label, parallel‐group studies were conducted. Participants with renal or hepatic impairment were matched with healthy controls and received a single 200‐mg dose of zilurgisertib; those with end‐stage renal disease (ESRD) received doses before and after haemodialysis. Plasma concentrations were quantified via validated assay; pharmacokinetic parameters were derived from non‐compartmental analysis. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for C max , AUC 0‐t and AUC 0‐∞ were compared by ANOVA. Results Compared with matched controls, GMRs (90% CIs) for C max and AUC 0‐∞ were as follows: mild renal impairment, 0.92 (0.64–1.34) and 0.98 (0.77–1.24); moderate, 1.22 (0.92–1.63) and 1.64 (1.28–2.10); severe, 1.00 (0.74–1.35) and 1.70 (1.33–2.16), respectively. Among participants with ESRD, values were the following: before haemodialysis, 1.17 (0.91–1.49) and 1.47 (1.15–1.88); after, 1.32 (1.00–1.75) and 1.68 (1.29–2.19), respectively. Among participants with hepatic impairment, values were as follows: moderate, 1.06 (0.80–1.42) and 1.13 (0.93–1.38); severe: 1.36 (1.05–1.76) and 1.25 (1.06–1.48), respectively. Conclusions Zilurgisertib exposure was unchanged with mild renal or moderate hepatic impairment, but increased by 30%–70% with moderate or more severe renal impairment and by 25% with severe hepatic impairment. These findings, alongside the therapeutic index, to be defined by the ongoing pivotal FOP trial (NCT05090891), will guide dosing in these populations.
DOI: 10.1002/bcp.70372
Institution: Incyte (United States)
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,780
Funder: Incyte
OpenAlex ID: W4417183454