PBPK Modeling to Predict Clinical Drug-Drug Interaction and Impact of Hepatic Impairment for an ADC With the Payload Auristatin F-Hydroxypropylamide.

ABSTRACT: Upifitamab rilsodotin-an antibody drug conjugate (ADC)-comprises a NaPi2b-targeted antibody conjugated to an auristatin-based payload (auristatin F-hydroxypropylamide [AF-HPA]). AF-HPA is metabolized by cytochrome P450 3A4 (CYP3A4) and, to a lower extent, by CYP3A5 and demonstrates both reversible and time-dependent inhibition of CYP3A4. AF-HPA is also a P-glycoprotein (P-gp) substrate. A PBPK model was developed using a mixed "bottom-up" and "top-down" modeling approach with a combination of in vitro, nonclinical, and clinical ADME/PK data. The model recapitulated the clinical PK of conjugated and unconjugated AF-HPA. Simulations were used to predict the potential of unconjugated AF-HPA to be a victim or perpetrator of clinical drug-drug interactions (DDI) and predict the impact of hepati

SUBMITTER: Kumar N 

PROVIDER: S-EPMC12521058 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature