Physiologically Based Pharmacokinetic Model to Assess the Influence of Blinatumomab‐Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity. (22nd August 2015)

• Record Type: Journal Article
• Authors: Xu, Y; Hijazi, Y; Wolf, A; Wu, B; Sun, Y‐N; Zhu, M
• Is Part Of: CPT: pharmacometrics & systems pharmacology. Volume 4:Number 9(2015:Sep.)
• Page Start: 507
• Page End: 515
• Publication Date: 2015-08-22
• Subjects: Pharmacokinetics -- Periodicals; Pharmacology -- Periodicals; Pharmacokinetics; Periodicals; 615.05
• DOI: 10.1002/psp4.12003
• Languages: English
• ISSNs: 2163-8306

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 &lt;30%, and IL‐6–mediated changes in exposure to sensitive substrates of CYP3A4, CYP1A2, and CYP2C9 were &lt;twofold and lasted &lt;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.</p> </abstract>