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

<b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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.