# Translational Pharmacokinetic-Pharmacodynamic Modeling of a Novel Oral Dihydroorotate Dehydrogenase (DHODH) Inhibitor, HOSU-53 (JBZ-001)

## TL;DR

This paper presents a pharmacokinetic-pharmacodynamic model for a new cancer drug, HOSU-53, to determine a safe starting dose for human trials.

## Contribution

The study introduces a translational PK/PD model for HOSU-53, a novel DHODH inhibitor, to recommend a first-in-human dose.

## Key findings

- A population PK/PD model accurately described HOSU-53's pharmacokinetics and pharmacodynamics in preclinical species.
- A first-in-human dose of 5 mg once daily was recommended based on model predictions.
- Physiologically based PK modeling predicted human hepatocellular concentrations of HOSU-53.

## Abstract

Background: HOSU-53 (JBZ-001), an orally bioavailable new chemical entity, represents a highly potent dihydroorotate dehydrogenase (DHODH) inhibitor in late preclinical development for application in cancer therapy. Methods: Multiple Good Laboratory Practice (GLP) and non-GLP preclinical studies were conducted in mice, rats, and dogs. Plasma samples of HOSU-53 and dihydroorotate (DHO), the substrate of DHODH, were collected for pharmacokinetic (PK) and pharmacodynamic (PD) assessment and modeling. Two modeling approaches were utilized to understand the PK/PD properties of HOSU-53 and to recommend a first-in-human (FIH) dose. Results: A population PK/PD model was developed using a stochastic approximation of the expectation-maximization method and evaluated using graphical and numerical methods. The PK of HOSU-53 was well described by a two-compartment model with a first-order absorption and linear elimination, and the PD was described by a turnover model. No covariates were considered significant on PK/PD parameters. This model was subsequently used to predict DHO exposures in humans across a range of doses. Additionally, predicted human hepatocellular HOSU-53 concentrations were obtained from a physiologically based PK model constructed in PK-Sim. Conclusions: A first-in-human starting dose of 5 mg once daily was established from the model approaches and will be utilized in the upcoming FIH clinical study.