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 hepatic impairment on the exposure to unconjugated AF-HPA. Simulations suggested negligible potential for clinical DDI between unconjugated AF-HPA and CYP3A substrates. Simulations also showed ~30% increase in unconjugated AF-HPA exposure following an IV dose of 36 mg/m² in the presence of itraconazole, an inhibitor of both CYP3A4 and P-gp. A negligible change in the exposure to unconjugated AF-HPA was predicted in patients with mild hepatic impairment, which aligned with observed clinical data. The model predicted a ~1.5-fold increase in unconjugated AF-HPA AUC and negligible change in the C_max in patients with moderate and severe hepatic impairment. Finally, this PBPK model may be applied (with modification to the conjugated drug sub-model parameters) to predict DDI and hepatic impairment potential for other ADCs with the same linker and payload.