Physiologically Based Pharmacokinetic Model to Predict Drug–Drug Interactions With the Antibody–Drug Conjugate Trastuzumab Deruxtecan

The topoisomerase I inhibitor payload (DXd) released from the human epidermal growth factor receptor 2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) is eliminated by hepatic uptake via OATP1B1/3, metabolism by CYP3A, biliary excretion via P-glycoprotein and breast cancer resistance protein, and urinary excretion. In a clinical drug-drug interaction (DDI) study between T-DXd and ritonavir (a strong cytochrome P450 [CYP] 3A/organic anion transporting polypeptide 1B inhibitor) or itraconazole (a strong CYP3A inhibitor), a 1.2-fold increase in DXd exposure was observed. In this study, a physiologically based pharmacokinetic (PBPK) model of T-DXd was constructed to quantitatively describe the pharmacokinetics (PK) of DXd and the DDI of DXd released from T-DXd. The minimal ADC PBPK model was developed to describe both intact ADC and payload PK using in vitro data of DXd and clinical PK data after T-DXd administration. The developed model reasonably described the PK of T-DXd and DXd after intravenous administration of T-DXd. The main elimination pathway of DXd was estimated to be biliary excretion, followed by urinary excretion, with metabolism contributing to a lesser extent. DDIs with ritonavir and itraconazole simulated by the PBPK model reproduced the clinical DDI study results, indicating that the impact of concomitant medications was not clinically meaningful. These findings suggest that this model may potentially be used for DDI evaluation of future DXd-containing ADCs, aiding in the prediction of DDIs under different scenarios and in specific populations.