Population pharmacokinetic-pharmacodynamic modeling of the iclepertin drug effect on hemoglobin levels
Nina Hanke (1), Peter Nagy (1), Corey Reuteman-Fowler (2), Mahmoud Tareq Abdelwahab (3), Samuel P. Callisto (4), Fredrik Gruenenfelder (1), Michael Desch (3)
(1) Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany, (2) Boehringer Ingelheim Pharma Inc., Ridgefield, CT, USA, (3) Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, (4) Metrum Research Group, Tariffville, CT, USA
Introduction: Iclepertin (BI 425809) is a novel, potent and selective glycine transporter-1 (GlyT1) inhibitor currently in Phase III development to help patients with cognitive impairment associated with schizophrenia (CIAS). Inhibition of GlyT1 in the presynaptic membranes increases the glycine concentration in the synaptic cleft, to enhance N-methyl-D-aspartate (NMDA) receptor signaling and is hypothesized to improve cognitive function and memory. However, glycine is also required for the first step of heme biosynthesis in the red blood cells. While inhibition of GlyT1 in the brain aims to improve cognition in schizophrenia patients, inhibition of GlyT1 in the cell membrane of erythrocyte precursors could possibly interfere with glycine uptake and heme biosynthesis, and consequently affect the production of hemoglobin.
Objectives: 1. Develop a population pharmacokinetic-pharmacodynamic (popPKPD) model to describe the impact of iclepertin exposure on hemoglobin levels. 2. Simulate the hemoglobin concentration-time course under chronic iclepertin treatment (365 days) to see if there will be a new hemoglobin steady-state and when this will be reached. 3. Assess the hypothetical risk of anemia for the worst-case scenario iclepertin exposure.
Methods: The model was developed based on blood measurements from 3 clinical iclepertin studies (n=25 healthy volunteers, n=599 Alzheimer’s Disease Dementia patients, n=492 Schizophrenia patients, EudraCT Numbers: 2014-005652-26, 2015-005438-24, 2016-000285-28), and a literature model describing the effect of the discontinued Roche GlyT1 inhibitor bitopertin on hemoglobin levels [1]. A previously developed popPK model was used to predict individual steady-state iclepertin exposure for all study participants (AUCss) [2]. The predicted PK exposure was then used in the popPKPD iclepertin-hemoglobin model to drive the iclepertin drug effect.
Blood hemoglobin concentrations (the investigated safety marker) are the product of mean corpuscular hemoglobin (MCH, hemoglobin mass per red blood cell) and the red blood cell count per liter (RBC). The model was developed by simultaneously fitting to both MCH and RBC observations. This allowed quantification of the impact of iclepertin GlyT1 inhibition on hemoglobin synthesis within the red blood cells (affecting the MCH production rate), and incorporation of the physiological feedback from changes in hemoglobin levels that regulate the red blood cell production (affecting the RBC production rate).
Results: The current best model consists of two parallel chains of 4 transit compartments each, representing the production, lifespan and elimination of the red blood cells (RBC) with their hemoglobin content (MCH). GlyT1 inhibition by iclepertin was implemented as proportional drug effect via an Emax relationship on the MCH production rate. The physiological hemoglobin feedback mechanism was modeled as a power function based on the relative hemoglobin change from baseline on the RBC production rate. The identified covariates are: sex, age, body mass index, race and liver function. No significant impact of kidney function could be identified.
Simulations show a decreased hemoglobin steady-state under chronic iclepertin treatment, reached after approximately 120-140 days. For a typical patient, the projected therapeutic dose of 10 mg iclepertin daily is predicted to decrease hemoglobin by 2.0%. The worst-case scenario of 5-times increased iclepertin exposure due to co-administration of a strong CYP3A4 inhibitor is predicted to decrease hemoglobin by 7.6%. Even for this worst-case scenario, 95% of the virtual patients stay above the defined hemoglobin safety thresholds of 100 g/L for women and 110 g/L for men.
Conclusions: The current model is able to describe the effects of chronic iclepertin administration on patient hemoglobin levels. The model serves as a platform to assess the risk of anemia in patients and vulnerable patient subpopulations, during untested administration scenarios, and to inform the need for monitoring.
References:
[1] Schaedeli Stark et al. 2012. PAGE 21 Abstract 2553 [www.page-meeting.org/?abstract=2553]
[2] Callisto et al. 2021. Internal Report c36250553
