Frontiers in pharmacology · 2026
Pharmacokinetic/pharmacodynamic analysis to characterize the effect of long-term GlyT1 inhibitor iclepertin exposure on hemoglobin levels.
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Hanke Nina, Callisto Samuel P, Nagy Peter, Desch Michael, Abdelwahab Mahmoud Tareq
Аннотация
BACKGROUND: This analysis was conducted to assess the risk of anemia in schizophrenia patients during long-term treatment with the glycine transporter-1 (GlyT1) inhibitor iclepertin.
METHODS: A population pharmacokinetic-pharmacodynamic (popPKPD) analysis to characterize the impact of iclepertin exposure on hemoglobin levels was performed using a sequential nonlinear mixed effects modeling approach. The effects of patient characteristics were investigated in a covariate analysis to identify vulnerable patient subgroups, and population simulations were conducted to evaluate different treatment scenarios.
RESULTS: Simulations predicted a new, decreased hemoglobin steady state under chronic iclepertin treatment, reached after approximately 120 days. For a typical patient, the intended therapeutic dose of 10 mg iclepertin daily led to a 2% decrease of hemoglobin levels. In a potential extreme scenario of iclepertin exposure fivefold higher than the average exposure following a 10 mg dose (e.g., due to co-administration of a strong CYP3A4 inhibitor), a 7.6% decrease of hemoglobin levels was found. In both scenarios more than 97.5% of the virtual patients stayed above the drug discontinuation safety threshold of 100 g/L hemoglobin (Phase III trial drug discontinuation threshold defined by the patient safety team). Sex, race, age, body mass index and alanine transaminase levels were found to correlate with changes in hemoglobin levels. No correlation with kidney function could be identified. None of the investigated covariate effects were strong enough to raise any safety concerns during chronic treatment with 10 mg iclepertin daily.
CONCLUSION: This work provides a generalizable modeling and simulation framework to assess the anemia risk in patients and vulnerable patient subgroups during chronic iclepertin treatment. The results of this analysis suggest that iclepertin drug effects on patient hemoglobin levels are small, reversible, and of limited significance, even under long-term treatment. This is the first model of the relationship between iclepertin exposure and hemoglobin levels, and, to our best knowledge, the first model to characterize a drug effect on hemoglobin levels over time that has been validated with clinical data that extend beyond the erythrocyte life span of ∼126 days.
METHODS: A population pharmacokinetic-pharmacodynamic (popPKPD) analysis to characterize the impact of iclepertin exposure on hemoglobin levels was performed using a sequential nonlinear mixed effects modeling approach. The effects of patient characteristics were investigated in a covariate analysis to identify vulnerable patient subgroups, and population simulations were conducted to evaluate different treatment scenarios.
RESULTS: Simulations predicted a new, decreased hemoglobin steady state under chronic iclepertin treatment, reached after approximately 120 days. For a typical patient, the intended therapeutic dose of 10 mg iclepertin daily led to a 2% decrease of hemoglobin levels. In a potential extreme scenario of iclepertin exposure fivefold higher than the average exposure following a 10 mg dose (e.g., due to co-administration of a strong CYP3A4 inhibitor), a 7.6% decrease of hemoglobin levels was found. In both scenarios more than 97.5% of the virtual patients stayed above the drug discontinuation safety threshold of 100 g/L hemoglobin (Phase III trial drug discontinuation threshold defined by the patient safety team). Sex, race, age, body mass index and alanine transaminase levels were found to correlate with changes in hemoglobin levels. No correlation with kidney function could be identified. None of the investigated covariate effects were strong enough to raise any safety concerns during chronic treatment with 10 mg iclepertin daily.
CONCLUSION: This work provides a generalizable modeling and simulation framework to assess the anemia risk in patients and vulnerable patient subgroups during chronic iclepertin treatment. The results of this analysis suggest that iclepertin drug effects on patient hemoglobin levels are small, reversible, and of limited significance, even under long-term treatment. This is the first model of the relationship between iclepertin exposure and hemoglobin levels, and, to our best knowledge, the first model to characterize a drug effect on hemoglobin levels over time that has been validated with clinical data that extend beyond the erythrocyte life span of ∼126 days.