029: Physiologically-based Pharmacokinetic Modeling of a Novel HER3-Targeted Antibody-Drug Conjugate, Patritumab Deruxtecan to Assess Pharmacokinetic Drug-Drug Interaction

Statement of Purpose, Innovation or Hypothesis: Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate (ADC) under investigation for the treatment of various cancers including non-small cell lung cancer. The payload molecule DXd is eliminated by hepatic uptake via OATP1B1/3, metabolism by CYP3A, biliary excretion via P-gp and BCRP, and urinary excretion. In a clinical drug-drug interaction (DDI) study between trastuzumab deruxtecan (T-DXd), which has the same linker and payload as HER3-DXd, and ritonavir (a strong CYP3A/OATP1B inhibitor) or itraconazole (a strong CYP3A inhibitor), approximately 1.2-fold increase in DXd AUC was observed [1]. The aim of this study is to inform the DDI risk of HER3-DXd by PBPK leveraging the available non-clinical and clinical information.

Description of Methods & Materials: The HER3-DXd PBPK model was constructed using the small molecule module of Simcyp Simulator V21 to treat HER3-DXd as a parent drug leading to the formation of DXd as a metabolite. The DXd PBPK model incorporating the parameters for hepatic uptake via OATP1B1/3, metabolism by CYP3A, biliary excretion via P-gp and BCRP, and urinary excretion, was already validated using the clinical DDI study results of T-DXd [2]. The HER3-DXd model validated using the clinical PK data [3] was applied to predict the effect of itraconazole and ritonavir on the DXd exposure following release from HER3-DXd. The impact of ADC clearance leading to release of DXd from HER3-DXd on the PK of DXd and the DDI risk was also evaluated.

Data & Results: The developed model reasonably described the PK profiles of HER3-DXd and DXd after intravenous administration of HER3-DXd. The Cmax and AUC ratios of DXd following a 5.6 mg/kg dose of HER3-DXd in the presence and absence of ritonavir or itraconazole were simulated to be 1.30 and 1.33 with ritonavir, and 1.18 and 1.19 with itraconazole, respectively. This result indicated that the simulated DDI effects were comparable with those observed in the clinical DDI study of T-DXd (Cmax and AUC ratios: 0.99 and 1.22 with ritonavir, and 1.04 and 1.18 with itraconazole, respectively). The sensitivity analysis of the ADC clearance showed that 10-fold changes had minimal impact on the predicted DDI with ritonavir or itraconazole, although they caused large changes in the PK profiles of DXd. This result suggested that the impact of these inhibitors on the DXd PK remained minimal even though the DXd PK was affected by the change of the ADC clearance.

Interpretation, Conclusion or Significance: The HER3-DXd PBPK model predicted strong CYP3A and OATP1B inhibitors would have minimal impact on DXd after HER3-DXd dosing, similar to the case of T-DXd. In addition, even if an ADC with the same payload (DXd) has different PK characteristics, such as difference in ADC clearance, it is considered that the impact of inhibitors on DXd released from ADC will generally be consistent. This study demonstrates the utility of ADC PBPK modeling and simulation to predict DDI risk of ADCs sharing the same payload.

Disclosures: AW, HA and MK are employees of Daiichi Sankyo Co., Ltd. LL, TG and MA are employees of Daiichi Sankyo, Inc. BC and KG are employees of Certara UK Ltd.

Citations/References: [1] Takahashi et. al., Clin Cancer Res 2021; 27: 5771-5780, [2] Watanabe et. al., Poster presentation in ACoP12 2021, [3] Jänne et. al., Cancer Discov 2022; 12(1): 74-89

Additional Information/Authors: n/a