Assessment of Telisotuzumab Vedotin Drug–Drug Interaction Potential Using Physiologically‐Based Pharmacokinetic Modeling and Simulations

Abstract Telisotuzumab vedotin (Teliso‐V; ABBV‐399) is an antibody‐drug conjugate (ADC) comprised of the c‐Met targeting antibody telisotuzumab (ABT‐700) conjugated to the potent cytotoxic monomethyl auristatin E (MMAE). Teliso‐V has been evaluated for treating solid tumors and is approved for adults with locally‐advanced or metastatic non‐squamous non‐small cell lung cancer with high c‐Met protein overexpression (≥50% tumor cells with strong +3 staining; determined by FDA‐approved test), who have received prior systemic therapy. Here, physiologically‐based pharmacokinetic (PBPK) modeling was utilized to evaluate Teliso‐V drug‐drug interaction (DDI) potential. A published PBPK‐model for MMAE as the primary metabolite and a newly‐developed telisotuzumab model from existing pre‐clinical and clinical trial data were used to create a novel Teliso‐V PBPK‐model. Unconjugated MMAE release was modeled with drug‐to‐antibody ratio‐specific deconjugation rates, with non‐specific and catabolic clearance added to capture half‐life and overall PK profile. The Teliso‐V model was calibrated and validated using observed clinical trial data, requiring dose‐normalized exposure %PEs ≤50%. CYP3A‐mediated DDI simulations demonstrated that when Teliso‐V was modeled as the victim, a 43% increase and 70% decrease in MMAE AUC were predicted with ketoconazole (strong CYP3A4‐inhibitor) and rifampin (strong CYP3A4‐inducer) coadministration, respectively. DDI magnitude was comparable to that observed between another approved ADC with the same MMAE payload (brentuximab vedotin) and ketoconazole and rifampin. The current PBPK simulations demonstrated a lack of perpetrator effect of Teliso‐V on midazolam, a sensitive CYP3A substrate. The current analysis provides important information on Teliso‐V DDI potential and further demonstrates the utility of PBPK models, particularly in oncology, where dedicated DDI studies are challenging.