**4. Drug-drug interactions**

#### **4.1 T-DM1**

There are no formal drug interaction studies with DM1. DM1 is extensively metabolized by CYP3A4, and it is anticipated that strong CYP3A4 inhibitors can increase DM1 concentrations and toxicity. Therefore, it is recommended that concomitant use of strong CYP3A4 inhibitors with T-MD1 is avoided. If concomitant use cannot be avoided, closely monitor for T-DM1 toxicities [14]. However, a phase I study evaluated the safety and efficacy of T-DM1 in combination with tucatinib, which is a strong CYP3A4 inhibitor revealed that DM1 concentration was similar to those reported in studies of T-DM1 monotherapy suggesting lack of clinically meaningful interactions [44]. The impact of strong CYP3A4 on T-DM1 has not been evaluated to date. DM1 does not inhibit or induce major CYP450 enzymes [14].

#### **4.2 T-DXd**

Dxd is a substrate of OATP1B1/3, MATE2-K, P-gp, MRP1, and BCRP. Coadministration of strong CYP3A4 inhibitors increased Dxd area under the curve (AUC) by 18%, and that was not considered clinically meaningful [15]. Coadministration of ritonavir, dual inhibitor of CYP3A4 and OATP1B increased Dxd AUC by 22%. The impact was not clinically significant. According to in vitro studies, DXd does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and
