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.