Drug Interaction Potential As a Result of Cytokine Release Syndrome Using a Physiologically Based Pharmacokinetic Model: Case Study of Teclistamab

Introduction: Teclistamab is a B-cell maturation antigen (BCMA) × CD3 bispecific IgG4 antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing multiple myeloma (MM) cells. Interleukin-6 (IL-6) is a biomarker of inflammation that is known to downregulate cytochrome P450 (CYP) enzyme activity. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the impact of IL-6 serum level observed in the MajesTEC-1 study at the recommended phase 2 dosing regimen (RP2D) of teclistamab (1.5 mg/kg subcutaneous weekly treatment dose, with the first treatment dose preceded by step-up doses of 0.06 and 0.3 mg/kg) on the exposure of coadministered CYP substrates.

Methods: A PBPK model was developed for IL-6 based on the literature (Xu Y et al. CPT Pharmacometrics Syst Pharmacol. 2015;4:507-15). Volume of distribution was modelled by a minimal PBPK model. Clearance was modelled nonmechanistically. Drug-drug interaction (DDI) toward different CYP substrates (caffeine [CYP1A2], s-warfarin [CYP2C9], omeprazole [CYP2C19], midazolam and cyclosporine [CYP3A4 and CYP3A5], and simvastatin [CYP3A4]) were evaluated where substrates were administered as a single dose when the minimum (or the maximum for CYP1A2) enzymatic activity was reached. First, ability of the PBPK model to capture such DDI was validated using data from the literature (Schmitt C et al. Clin Pharmacol Ther. 2011;89:735-40; Jiang X et al. AAPS J. 2016;18:767-76). Then, prospective simulations were performed using observed IL-6 data following teclistamab administered at RP2D without or prior to tocilizumab administration in MajesTEC-1 as of a March 16, 2022, cut-off. Observed data were recovered by adjusting the dosing regimen of IL-6, modelled as an intravenous infusion. Two scenarios were envisioned: the observed IL-6 mean serum profile and the worst-case scenario, corresponding to the IL-6 profile observed in the patient presenting the highest IL-6 C_max value. In addition, the time to reach the maximum change in CYP activity due to IL-6, and the return to 80% of the baseline enzymatic activity, were evaluated, with the start of cycle 1 as reference.

Results: Observed DDIs from literature with CYP1A2, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 substrates in the presence of steady state concentrations of IL-6 at 50 pg/mL were well predicted, providing confidence in the application of the model to assess IL-6 as a perpetrator of these CYP substrates. Using the PBPK model, the IL-6 kinetic profile following teclistamab administered at RP2D was predicted to result in a limited change in exposure of CYP1A2, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 substrates (0.87 ≤ area under the curve [AUC] ratio ≤ 1.20) when mean IL-6 profile was considered (mean C_max = 21 pg/mL). When the IL-6 kinetic profile with the highest C_max (288 pg/mL) was considered, the impact on the exposure of CYP2C19, CYP3A4, and CYP3A5 substrates (eg, omeprazole, simvastatin, cyclosporine) could be moderate (1.90 ≤ AUC ratio ≤ 2.23), and the impact on the exposure of CYP1A2 and CYP2C9 substrates (eg, caffeine and s-warfarin) was minimal (AUC ratio = 0.82 and 1.25, respectively). For both scenarios, the maximum change in exposure for the studied substrates occurred 3 to 4 days after the start of cycle 1. For the patient with the highest IL-6 C_max, return to 80% of the baseline enzymatic activity was observed approximately 7 days after the start of cycle 1.

Conclusions: PBPK modeling and simulation results suggested DDI from IL-6 effect on CYP450 activities to have little clinical significance with minimal or moderate impact on CYP substrates up to 7 days after teclistamab first treatment dose in cycle 1 or during a cytokine release syndrome event.

Willemin:Janssen Pharmaceutical: Current Employment. Wang Lin:Janssen: Current equity holder in private company, Ended employment in the past 24 months. De Zwart:Janssen: Current Employment. Wu:Johnson & Johnson: Current Employment. Miao:Janssen: Current Employment. Verona:Janssen R&D, Johnson and Johnson: Current Employment. Banerjee:Janssen R&D: Current Employment, Current equity holder in publicly-traded company. Kobos:Janssen: Current equity holder in private company, Current holder of stock options in a privately-held company. Qi:Janssen: Current Employment, Current equity holder in publicly-traded company. Ouellet:Johnson & Johnson (Janssen): Current Employment, Current holder of stock options in a privately-held company; Abbvie: Current equity holder in private company; Pfizer Inc: Ended employment in the past 24 months. Goldberg:Janssen: Current Employment, Current equity holder in private company. Girgis:Janssen Research & Development, Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company.

at the time of abstract submission, teclistamab is being investigated for the treatment of multiple myeloma but is not yet not approved