# Development of a Physiologically Based Model of Bilirubin Metabolism in Health and Disease and Its Comparison With Real‐World Data

## TL;DR

This study creates a computational model of bilirubin metabolism to understand how it works in health and disease, and how drugs affect it.

## Contribution

The first model to compare simulated bilirubin metabolism with real-world clinical data, capturing disorder-specific patterns and drug effects.

## Key findings

- Gilbert syndrome requires significant UDP-glucuronosyltransferase 1A1 activity reduction.
- Crigler-Najjar syndrome needs near-complete loss of UDP-glucuronosyltransferase 1A1 function.
- Atazanavir increases unconjugated bilirubin more in Gilbert syndrome patients than in healthy individuals.

## Abstract

Bilirubin is a breakdown product of erythrocytes and plays a crucial role in elimination of heme‐containing proteins. After its synthesis in the reticuloendothelial system, unconjugated bilirubin is released into plasma and taken up into the liver. In hepatocytes, bilirubin is conjugated and excreted into the gastrointestinal tract via bile, where it is further converted to urobilinoids. There are various genetic factors causing abnormal bilirubin levels in plasma, such as Gilbert syndrome, Crigler‐Najjar syndrome, Dubin‐Johnson syndrome, and Rotor syndrome. To better understand bilirubin metabolism and its disorders, this study develops a physiologically based computational model incorporating published literature as well as real‐world clinical data from the Explorys database. The model simulates bilirubin levels in both healthy individuals and patients with disorders of bilirubin metabolism. Population simulations show that Gilbert syndrome requires a substantial reduction in UDP‐glucuronosyltransferase 1A1 activity, while Crigler‐Najjar syndrome requires near‐complete loss of its function. In contrast, Dubin‐Johnson syndrome is characterized by a significant impairment of multidrug resistance‐associated protein 2 activity. To also illustrate model behavior under targeted perturbations, we simulated administration of atazanavir in healthy individuals and patients with Gilbert syndrome to investigate its effect on bilirubin levels. Relative to baseline, unconjugated bilirubin maximum concentration (C
max) increased by 34% in healthy individuals but by 67% in Gilbert syndrome. Overall, this study provides a conceptual and mechanistically informed framework for studying bilirubin homeostasis and the functional consequences of drug administration in health and disease.

What is the current knowledge on the topic?
○Bilirubin metabolism involves breakdown of heme into unconjugated bilirubin, which is then conjugated in the liver and excreted into the bile. Disorders such as Gilbert syndrome, Crigler‐Najjar syndrome, Dubin‐Johnson syndrome, and Rotor syndrome disrupt this process, leading to abnormal bilirubin levels.
What question did this study address?
○We developed a whole‐body physiologically based computational model representing bilirubin metabolism to evaluate the bilirubin levels in health and bilirubin‐related disorders, addressing interindividual variability, disorder‐specific mechanistic alterations, and effects of dynamic perturbations.
What does this study add to our knowledge?
○The study presents functional analyses of bilirubin homeostasis and specific metabolic disorders. It is the first study to systematically compare simulations of bilirubin metabolism with real‐world clinical data, providing insights into interindividual variability and disorder‐specific patterns.
How might this change drug discovery, development, and/or therapeutics?
○The model provides a conceptual and mechanistic framework for investigation of drug‐induced perturbations in bilirubin metabolism. The model can in particular be used to explore aberrant states in vulnerable patient subgroups with specific metabolic disorders at the population level.

What is the current knowledge on the topic?
○Bilirubin metabolism involves breakdown of heme into unconjugated bilirubin, which is then conjugated in the liver and excreted into the bile. Disorders such as Gilbert syndrome, Crigler‐Najjar syndrome, Dubin‐Johnson syndrome, and Rotor syndrome disrupt this process, leading to abnormal bilirubin levels.

Bilirubin metabolism involves breakdown of heme into unconjugated bilirubin, which is then conjugated in the liver and excreted into the bile. Disorders such as Gilbert syndrome, Crigler‐Najjar syndrome, Dubin‐Johnson syndrome, and Rotor syndrome disrupt this process, leading to abnormal bilirubin levels.

What question did this study address?
○We developed a whole‐body physiologically based computational model representing bilirubin metabolism to evaluate the bilirubin levels in health and bilirubin‐related disorders, addressing interindividual variability, disorder‐specific mechanistic alterations, and effects of dynamic perturbations.

We developed a whole‐body physiologically based computational model representing bilirubin metabolism to evaluate the bilirubin levels in health and bilirubin‐related disorders, addressing interindividual variability, disorder‐specific mechanistic alterations, and effects of dynamic perturbations.

What does this study add to our knowledge?
○The study presents functional analyses of bilirubin homeostasis and specific metabolic disorders. It is the first study to systematically compare simulations of bilirubin metabolism with real‐world clinical data, providing insights into interindividual variability and disorder‐specific patterns.

The study presents functional analyses of bilirubin homeostasis and specific metabolic disorders. It is the first study to systematically compare simulations of bilirubin metabolism with real‐world clinical data, providing insights into interindividual variability and disorder‐specific patterns.

How might this change drug discovery, development, and/or therapeutics?
○The model provides a conceptual and mechanistic framework for investigation of drug‐induced perturbations in bilirubin metabolism. The model can in particular be used to explore aberrant states in vulnerable patient subgroups with specific metabolic disorders at the population level.

The model provides a conceptual and mechanistic framework for investigation of drug‐induced perturbations in bilirubin metabolism. The model can in particular be used to explore aberrant states in vulnerable patient subgroups with specific metabolic disorders at the population level.