# Pre-Emptive Drug Safety Evaluation of Iclepertin (BI-425809) Using Real-World Data and Virtual Addition of This Medication to the Actual Drug Regimen of Individuals from Large Populations

## TL;DR

This study uses real-world data to predict the safety of a new drug, iclepertin, by simulating its effects on a large population without actual patient exposure.

## Contribution

The study introduces a novel method for pre-emptive drug safety evaluation using biosimulation and real-world data.

## Key findings

- Adding iclepertin increased medication risk scores in about 50% of the population, with most experiencing a 2-unit increase.
- The drug's addition led to a 0.33% increase in individuals classified in the High/Severe risk category.
- CYP3A4 interactions were the main driver of increased risk, with a greater effect in individuals already on CYP3A4 perpetrator drugs.

## Abstract

Introduction. Adverse drug events (ADEs) are between the third and sixth most common cause of death worldwide. Biosimulation studies performed using real-world data could generate relevant drug safety information without exposing patients to ADEs. Methods. Iclepertin (BI-425809) was virtually added to the actual drug regimens of n = 4,405,063 individuals. Changes in risk level were estimated for drug-induced long QT syndrome and CYP450 drug interactions. The properties used for iclepertin included: dose of 10 mg (oral) once daily; bioavailability (F) = 71%; Cmax of 222 nM; CYP3A4 weak affinity substrate (partial metabolic clearance of ~80%); IC50 for hERG block of 30 μM. Results. A change in total medication risk score (MRS) was observed (6.3 ± 6.6 to 7.2 ± 6.6) following the addition of iclepertin in ~50% (n = 2,138,247) of the studied population. Among individuals with a change in MRS, ~65% had a 2-unit increase (max 11 units). The number of individuals classified in the High/Severe MRS category increased by 0.33%. The addition of iclepertin to individuals receiving CYP3A4 perpetrator drugs produced a greater change in MRS (+1.5) when compared to individuals not exposed to CYP3A4 perpetrators (+0.8). An additional 0.0032% of the population (n = 139) would be at risk of QT prolongation following the intake of iclepertin. Subset analyses performed in individuals with schizophrenia (targeted indication) demonstrated that these individuals had higher MRS values (13.0 ± 10.3) compared to those without schizophrenia (6.2 ± 6.9). However, the addition of iclepertin did not produce a greater increase in MRS in the schizophrenia population vs. the control population. Our pharmacoeconomic model did not account for any beneficial effects of the drug but the model based on MRS changes predicted a USD 91 yearly increase in medical expenditures (emergency department visits and hospitalizations) per individual (USD 3172 to USD 3263) following the addition of iclepertin. A similar increase was observed in the schizophrenia population following iclepertin addition. Conclusions. The increase in MRS associated with the addition of iclepertin to the drug regimen of a large population was minimal and mostly driven by CYP3A4 interactions. Using this model, interactions can be identified a priori, making risk mitigable and preventable without exposing patients to toxicity.