Background and Objectives <p>Iclepertin, a selective GlyT1 inhibitor undergoes metabolism mainly via hepatic CYP3A4, with only a small fraction undergoing urinary excretion. Patients with kidney or liver problems can have reduced CYP3A4 levels or activity, which may affect the levels of iclepertin in the blood and, in turn, its safety. Here, we present the results of two studies investigating the safety and pharmacokinetics of iclepertin in participants with various degrees of renal or hepatic impairment.</p> Methods <p>In these two phase I, open-label, non-randomised, parallel studies, a single oral dose of iclepertin 10 mg was administered to participants with mild, moderate or severe renal impairment or mild or moderate hepatic impairment, together with healthy matched participants (based on age, sex, weight and race [only for renal impairment]; <i>n</i> = 8 for each impairment group. Primary and secondary endpoints included maximum plasma concentration (<i>C</i>_max) and exposure metrics (area under the concentration-time curve [AUC]) of iclepertin. Safety was also assessed (adverse events [AEs]).</p> Results <p>In the renal impairment study (<i>N</i> = 36), exposure of iclepertin was minimally affected by renal impairment across trial groups except for the severe renal impairment group, which showed increased iclepertin exposure (AUC_0–tz and AUC_0–∞ geometric mean ratio impaired versus matched participants [90% CI]: 126.1% [104.1, 152.8] and 146.0% [109.9, 193.9]), but similar <i>C</i>_max. In the hepatic impairment study (<i>N</i> = 29), participants with mild hepatic impairment showed similar <i>C</i>_max of iclepertin and exposure parameters to matched participants (geometric mean ratio [90% CI]: 102.1% [82.4, 126.4]), whereas participants with moderate hepatic impairment showed reduced <i>C</i>_max (geometric mean ratio impaired versus matched participants [90% CI]: 81.9% [67.2, 99.7]) and increased AUC_0–tz and AUC_0–∞ (128.7% [104.0, 159.3] and 157.2% [119.1, 207.5], respectively. Headache was the only drug-related AE reported in &gt; 1 participant in each study, which was resolved within the treatment period, and no severe AEs were reported.</p> Conclusions <p>These findings indicate that although some increased exposure to iclepertin is expected in patients with severe renal impairment or moderate hepatic impairment, iclepertin 10 mg demonstrated a favourable safety profile, was well-tolerated, and can be administered in patients with varying degrees of renal or hepatic impairment without dose modification.</p> Study Registration <p>ClinicalTrials.gov (NCT05718843, NCT05731895).</p>