Evaluating drug interaction potential from cytokine release syndrome using a physiologically based pharmacokinetic model: A case study of teclistamab

Abstract

Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC‐1 study. Cytokines, especially interleukin (IL)‐6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL‐6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5). Two IL‐6 kinetics profiles were assessed, the mean IL‐6 profile with a maximum concentration ( C _max) of IL‐6 (21 pg/mL) and the IL‐6 profile of the patient presenting the highest IL‐6 C _max (288 pg/mL) among patients receiving the recommended phase II dose of teclistamab in MajesTEC‐1. For the mean IL‐6 kinetics profile, teclistamab was predicted to result in a limited change in exposure of CYP substrates (area under the curve [AUC] mean ratio 0.87–1.20). For the maximum IL‐6 kinetics profile, the impact on omeprazole, simvastatin, midazolam, and cyclosporine exposure was weak to moderate (mean AUC ratios 1.90–2.23), and minimal for caffeine and s‐warfarin (mean AUC ratios 0.82–1.25). Maximum change in exposure for these substrates occurred 3–4 days after step‐up dosing in cycle 1. These results suggest that after cycle 1, drug interaction from IL‐6 effect has no meaningful impact on CYP activities, with minimal or moderate impact on CYP substrates. The highest risk of drug interaction is expected to occur during step‐up dosing up to 7 days after the first treatment dose (1.5 mg/kg subcutaneously) and during and after CRS.