In Bethesda, Washington D.C., the ACCP annual meeting took place in 2024. Global DDI Solution was present at booth 6. This meeting is known for topics on clinical pharmacology and new drug developments. At the exciting meeting, a couple of posters were presented on the risk of drug-drug interactions (DDIs) with new (unregistered) drugs. Three of the posters are summarized below:

Poster 24: The Drug-Drug Interaction Effect of Steady-state Rifampin Exposure on Single-dose Pharmacokinetics of Lazertinib; Mehta et al.

Lazertinib, in combination with amivantamab, is indicated for locally advanced or metastatic NSCLC with EGFR mutation exon 19 or exon 21. Since 2019, lazertinib has been registered by the FDA but not yet by the EMA. In the study of Mehta et al., a Phase I, open-label, two-period, and fixed sequence healthy adult participant study, the clinical relevance of CYP3A4-mediated DDIs with Lazertinib as the victim was evaluated. They found that the coadministration of lazertinib with strong CYP3A4 inducer rifampin significantly decreased lazertinib plasma exposure. The coadministration of lazertinib with strong CYP3A4 inducers should be avoided.

Poster 26: Phase 1 Open-label Study to Evaluate the Effects of Savolitinib on the Pharmacokinetics of P-gp, OATP1B1/3, OCT2, MATE1/2K & OAT1/3 Substrates in Healthy Volunteers; Miah et al.

Savolitinib is a selective small molecule hepatocyte growth factor receptor (MET) kinase inhibitor and can be used in different types of cancer. In vitro, savolitinib is a P-gp substrate and weak OCT2 and OATP1B1/3 inhibitor. The metabolite M2 of savolitinib may also inhibit MATE1/2K and OAT1/3. This study evaluated the clinical DDI between savolitinib and metformin, digoxin, rosuvastatin, and furosemide. They found a comparable systemic exposure of digoxin, rosuvastatin, and furosemide following administration with savolitinib when dosed alone. So, savolitinib does not inhibit P-gp, OATP1B1/3 or OAT1/3. Savolitinib appeared to be a weak inhibitor of MATE1/2K and OCT2 in the clinic due to a change in metformin systemic exposure.

Poster 29: Physiologically-based Pharmacokinetic Modeling of a Novel HER3-Targeted Antibody-drug Conjugate, Patritumab Deruxtecan to Assess Pharmacokinetic Drug-Drug Interaction; Watanabe et al.

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate for various cancers, including NSCLC. A clinical DDI study between trastuzumab deruxtecan (same linker and payload as HER3-DXd) and ritonavir (potent CYP3A/OATP1B inhibitor) or itraconazole (strong CYP3A inhibitor) observed an approx. 1.2-fold increase in trastuzumab deruxtecan AUC. This study aims to inform about the DDI risk of HER3-DXd by physiologically-based pharmacokinetic (PBPK) modeling. Similar to the previous research on trastuzumab deruxtecan, HER3-DXd would be minimally influenced by strong CYP3A and OATP1B inhibitors. In addition, antibody-drug conjugates with the same payload have different PK characteristics, such as clearance.