Research report: 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

A single 10 mg dose of the experimental schizophrenia drug iclepertin produced higher blood exposure in people with severe kidney impairment or moderate liver impairment, yet the drug remained generally safe and well tolerated across all degrees of organ impairment tested, according to two Phase I studies published in the journal Drugs in R&D. The findings suggest that patients with mild to severe renal impairment or mild to moderate hepatic impairment may be able to take the drug without any dose adjustment, although the authors caution that the small sample sizes leave room for uncertainty.

Iclepertin, also known as BI 425809, is a selective inhibitor of the glycine transporter GlyT1 and has been investigated as a potential treatment for cognitive impairment associated with schizophrenia, a condition that affects roughly 80 to 90 percent of people with schizophrenia and for which no pharmacological treatment is currently approved. The drug is metabolised primarily, more than 90 percent, by the liver enzyme CYP3A4, forming two pharmacologically inactive metabolites, and less than 10 percent of the dose is excreted in urine. Because both kidney and liver disease can reduce the levels or activity of CYP3A4, the researchers reasoned that impaired organ function could raise drug exposure and potentially increase safety risks, making a dedicated investigation essential.

The two studies were Phase I, open-label, non-randomised, single-dose, parallel-design trials registered with ClinicalTrials.gov under identifiers NCT05718843 and NCT05731895. Participants with organ impairment were individually matched with healthy volunteers by sex, race in the renal study only, age within ten years, and weight within 15 percent. Each participant received a single oral 10 mg tablet of iclepertin after fasting overnight for at least ten hours, and serial blood samples were collected over the following days to characterise the drug’s pharmacokinetic profile.

The renal impairment study enrolled 36 participants: eight each with mild, moderate or severe renal impairment, defined by estimated glomerular filtration rate ranges of 60 to 89, 30 to 59, and 15 to 29 mL/min/1.73 m² respectively, plus 12 healthy matched participants with normal renal function. The hepatic impairment study enrolled 29 participants: eight with mild hepatic impairment, defined as a Child–Pugh score of 5 to 6, eight with moderate impairment, a Child–Pugh score of 7 to 9, and 13 healthy matched participants. Some healthy volunteers served as matches for more than one impaired participant, a design choice consistent with US Food and Drug Administration guidance recommending eight participants per study arm.

The primary endpoints were the maximum plasma concentration of iclepertin, known as Cmax, and total drug exposure measured as the area under the concentration-time curve, or AUC. In the renal study, exposure was minimally affected in the mild and moderate impairment groups, with parameter differences versus matched participants ranging from a 4 percent decrease to a 17 percent increase. The severe renal impairment group, however, showed markedly increased exposure: the geometric mean ratio for AUC from time zero to the last quantifiable point was 126.1 percent with a 90 percent confidence interval of 104.1 to 152.8, and for AUC extrapolated to infinity it was 146.0 percent with a 90 percent confidence interval of 109.9 to 193.9, corresponding to increases of 26 and 46 percent, while Cmax remained similar to matched participants.

Supporting parameters reinforced this picture. The apparent clearance of iclepertin was slower in the severe renal impairment group, 33.9 versus 49.3 mL/min, and the half-life was longer, 82.6 versus 65.1 hours. The metabolite BI 758790, which is excreted renally, showed increased exposure of up to 60 percent in severe renal impairment, likely reflecting reduced renal clearance of the metabolite itself, whereas BI 761036, which is not renally excreted, showed a slight exposure decrease. The authors interpret the raised parent-drug exposure as possibly stemming from uraemic toxins that accumulate in kidney failure and inhibit CYP3A4 activity, though they note no clear relationship between the degree of renal impairment and exposure overall.

In the hepatic impairment study, participants with mild liver impairment showed pharmacokinetics essentially comparable to matched participants, with a Cmax geometric mean ratio of 102.1 percent and a 90 percent confidence interval of 82.4 to 126.4. Participants with moderate hepatic impairment, by contrast, showed reduced Cmax, a geometric mean ratio of 81.9 percent with a 90 percent confidence interval of 67.2 to 99.7, alongside increased exposure: AUC to the last quantifiable point rose 29 percent, with a ratio of 128.7 percent and a 90 percent confidence interval of 104.0 to 159.3, and AUC to infinity rose 57 percent, with a ratio of 157.2 percent and a 90 percent confidence interval of 119.1 to 207.5. The half-life nearly doubled and apparent clearance fell almost two-fold, from 72.2 to 46.0 mL/min, while renal clearance remained comparable to healthy participants, a pattern the authors attribute to reduced CYP3A4-mediated metabolism. Exposure to both inactive metabolites was reduced in moderate hepatic impairment, consistent with impaired biotransformation of the parent compound.

The hepatic study also examined plasma protein binding of iclepertin using equilibrium dialysis and radio-HPLC analysis. The mean unbound fraction was 18.2 plus or minus 3.2 percent in mild hepatic impairment and 18.8 plus or minus 4.1 percent in moderate impairment, compared with roughly 17.4 to 17.6 percent in matched healthy participants, indicating no notable difference in protein binding across hepatic function groups and agreement with previously determined unbound fraction data.

Safety results were reassuring in both trials. Adverse events occurred in 17 percent of participants in the renal study and 21 percent in the hepatic study, all of which resolved by the end of the trials, and no severe adverse events were reported in either study. Headache was the only drug-related adverse event reported in more than one participant in each study, resolving within a day during the treatment period. Other drug-related events included single cases of increased lipase and hypertension in the renal study, and single cases of increased amylase, increased lipase and hypertension in the hepatic study.

The authors conclude that mild or moderate renal impairment and mild hepatic impairment did not have a clinically relevant effect on iclepertin pharmacokinetics, while severe renal impairment and moderate hepatic impairment produced some increase in exposure. They caution that the limited sample sizes, though in line with regulatory guidance, may explain variability observed in the matched participant groups of the hepatic study, and that the hepatic study included only mild and moderate impairment. Larger studies in broader cohorts, they note, would help confirm whether these single-dose findings generalise, and the results apply to a single 10 mg dose rather than the repeated once-daily dosing used in chronic treatment.

Subject of Research: Pharmacokinetics and safety of the GlyT1 inhibitor iclepertin in people with renal or hepatic impairment

Article Title: 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

Article References: Choi, H., Madari, S., Daalman, E., English, B. A., Halabi, A., Hohl, K., Shatillo, Y., Weidinger, N., & Desch, M. (2026). 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. Drugs in R&D, 26(1), 83-100. https://doi.org/10.1007/s40268-026-00537-w

Image Credits: AI Generated

DOI: 10.1007/s40268-026-00537-w

Keywords: iclepertin, BI 425809, pharmacokinetics, renal impairment, hepatic impairment, CYP3A4, schizophrenia, GlyT1 inhibitor, Phase I trials, drug exposure, dose adjustment, Drugs in R&D