The Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Iclepertin (BI 425809): Results from Two Phase I Open-Label, Non-randomised, Single Dose, Parallel Design Studies.
HeeJae Choi, Shilpa Madari, Elmar Daalman, Brett A English, Atef Halabi, Kathrin Hohl, Yury Shatillo, Nathalie Weidinger, Michael Desch
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引用次数: 0
Abstract
Background and objectives: 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.
Methods: 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]; n = 8 for each impairment group. Primary and secondary endpoints included maximum plasma concentration (Cmax) and exposure metrics (area under the concentration-time curve [AUC]) of iclepertin. Safety was also assessed (adverse events [AEs]).
Results: In the renal impairment study (N = 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 (AUC0-tz and AUC0-∞ geometric mean ratio impaired versus matched participants [90% CI]: 126.1% [104.1, 152.8] and 146.0% [109.9, 193.9]), but similar Cmax. In the hepatic impairment study (N = 29), participants with mild hepatic impairment showed similar Cmax 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 Cmax (geometric mean ratio impaired versus matched participants [90% CI]: 81.9% [67.2, 99.7]) and increased AUC0-tz and AUC0-∞ (128.7% [104.0, 159.3] and 157.2% [119.1, 207.5], respectively. Headache was the only drug-related AE reported in > 1 participant in each study, which was resolved within the treatment period, and no severe AEs were reported.
Conclusions: 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.
Study registration: ClinicalTrials.gov (NCT05718843, NCT05731895).
期刊介绍：
Drugs in R&D is an international, peer reviewed, open access, online only journal, and provides timely information from all phases of drug research and development that will inform clinical practice. Healthcare decision makers are thus provided with knowledge about the developing place of a drug in therapy.
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Clinical research on new and established drugs;
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Short communications and case study reports that meet the above criteria will also be considered;
Reviews may also be considered.
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