PII-003 - EVALUATION OF DRUG-DRUG INTERACTION (DDI) POTENTIAL FOLLOWING EPCORITAMAB TREATMENT: RESULTS FROM EXPANSION OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL.

T. Li¹, A. Parikh², C. Passey¹, M. Sacchi¹, M. Gupta¹, S. Xu¹; ¹Genmab, ²AbbVie Inc..

Background: Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, is approved by the US FDA for the treatment (tx) of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic tx. Epcoritamab may increase circulating levels of interleukin 6 (IL-6), a suppressor of cytochrome P450 (CYP) enzymes, suggesting DDI potential. We assessed epcoritamab DDI potential in patients with B-cell non-Hodgkin lymphoma in the phase 1/2 EPCORE™ NHL-1 trial (NCT03625037) using a PBPK model predicting CYP enzyme suppression based on elevated IL-6.

Methods: Patients received epcoritamab SC (step-up doses of 0.16 and 0.8 mg, then 48 mg full doses) in 28-day (d) cycles (Cs; QW, C1–3; Q2W, C4–9; Q4W, C≥10). Six time windows (Ws) were used for analysis: W1, D1–7; W2, D8–14; W3, D15–21; W4, D22–28; W5, D29–35; W6, D36–56 (dosing on D1, 8, 15, 22, 29). Model-simulated IL 6 concentrations were calibrated conservatively to match median observed EPCORE NHL-1 Cmax in each W. Caffeine, S warfarin, omeprazole, dextromethorphan, simvastatin, and midazolam (CYP substrates) dosing was simulated in each W. The PBPK model simulated effects of elevated IL-6 on CYP enzyme activities and substrate exposure to assess DDI potential.

Results: The conservative IL-6 profile based on median observed Cmax had a small, transient effect on CYP enzyme activities (20% reduction) in W3 (following first full epcoritamab dose), which quickly returned to baseline, and minimal suppression in all other Ws. A small, transient effect on AUC and Cmax was observed for some substrates (Figure). No clinically significant DDIs were predicted, with geometric mean ratios (GMRs) for AUC and Cmax of < 1.25 for CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) substrates. In W3, the highest predicted AUC or Cmax GMR for CYP2C19 (omeprazole) and CYP3A4/5 (simvastatin; midazolam) substrates was 1.31 (not clinically meaningful).

Conclusion: IL-6 release induced by epcoritamab tx is predicted to have a small, transient effect on CYP enzyme activities and substrate exposure. Epcoritamab is expected to have no clinically meaningful DDI potential, consistent with absence of contraindications in the US label.