Physiologically Based Pharmacokinetic Model to Assess the Influence of Blinatumomab-Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity

Abstract

Blinatumomab is a CD19/CD3 bispecific T-cell engager (BiTE®) antibody construct for treatment of leukemia. Transient elevation of cytokines (interleukin (IL)-6, IL-10, interferon-gamma (IFN-γ)) has been observed within the first 48 hours of continuous intravenous blinatumomab infusion. In human hepatocytes, blinatumomab showed no effect on cytochrome P450 (CYP450) activities, whereas a cytokine cocktail showed suppression of CYP3A4, CYP1A2, and CYP2C9 activities. We developed a physiologically based pharmacokinetic (PBPK) model to evaluate the effect of transient elevation of cytokines, particularly IL-6, on CYP450 suppression. The predicted suppression of hepatic CYP450 activities was <30%, and IL-6-mediated changes in exposure to sensitive substrates of CYP3A4, CYP1A2, and CYP2C9 were <twofold and lasted <1 week. Model verification indicated that IL-6 was the key cytokine suppressing CYP450 activities; the duration of cytokine elevation was a major determinant of magnitude of suppression. This study shows the utility of PBPK modeling for risk assessment of cytokine-mediated drug interactions.

Figure 1

(a) Serum peak cytokine concentrations after initiation of blinatumomab, (b) cytokine concentrations over time in an individual patient after initiation of blinatumomab, and (c) CRP concentrations over time by blinatumomab dose (n = 4–13 for each dose group). The dose group of ≤5 μg/m²/day combined patients' doses at 0.5, 1.5, and 5 μg/m²/day. CRP, C-reactive protein; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor alpha.

Figure 2

(a) Mean concentration-vs.-time profile of IL-6 following continuous intravenous infusion of blinatumomab and (b) IL-6 profile from a patient with the highest level of IL-6 elevation. CYP, cytochrome P450; EC₅₀, half-maximal effective concentration; IL, interleukin.

Figure 3

Predicted duration and magnitude of IL-6 suppression on hepatic CL_int of (a) CYP3A4, as measured by CL_int of simvastatin, (b) CYP1A2, as measured by CL_int of theophylline N1-demethylation, and (c) CYP2C9, as measured by CL_int of (S)-warfarin, based on the mean IL-6 profile in clinical trials of blinatumomab. (d) Predicted duration and magnitude of IL-6–mediated changes in simvastatin exposure. CL_int, intrinsic clearance; CYP, cytochrome P450; IL, interleukin. Percentages shown are for maximal reductions observed.

Figure 4

Predicted time course of IL-6 suppression on CL_int of CYP3A4 at constant IL-6 concentrations (50, 100, and 500 pg/mL) for 3 weeks, as measured by CL_int of simvastatin. CL_int, intrinsic clearance; CYP, cytochrome P450; IL, interleukin.