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

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/m 2 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.