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

Xu Y, Hijazi Y, Wolf A, Wu B, Sun YN, Zhu M - CPT Pharmacometrics Syst Pharmacol (2015)

Bottom Line: 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.This study shows the utility of PBPK modeling for risk assessment of cytokine-mediated drug interactions.

View Article: PubMed Central - PubMed

Affiliation: Amgen, Clinical Pharmacology, Modeling and Simulation Group, Department of Medical Sciences Thousand Oaks, California, USA.

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

No MeSH data available.


Related in: MedlinePlus

Predicted duration and magnitude of IL-6 suppression on hepatic CLint of (a) CYP3A4, as measured by CLint of simvastatin, (b) CYP1A2, as measured by CLint of theophylline N1-demethylation, and (c) CYP2C9, as measured by CLint 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. CLint, intrinsic clearance; CYP, cytochrome P450; IL, interleukin. Percentages shown are for maximal reductions observed.
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fig03: Predicted duration and magnitude of IL-6 suppression on hepatic CLint of (a) CYP3A4, as measured by CLint of simvastatin, (b) CYP1A2, as measured by CLint of theophylline N1-demethylation, and (c) CYP2C9, as measured by CLint 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. CLint, intrinsic clearance; CYP, cytochrome P450; IL, interleukin. Percentages shown are for maximal reductions observed.

Mentions: The established PBPK model was used to project the effect of the mean IL-6 dynamic profile on CYP450 enzymes in patients treated with blinatumomab. The changes in hepatic intrinsic clearance of CYP3A4, CYP1A2, and CYP2C9 marker substrates over time were simulated with the model. The maximal suppression on intrinsic hepatic clearance of CYP3A4 was 28%, occurred at ∼48 hours, and lasted for ∼1 week (Figure3a). Similarly, the maximal suppression on intrinsic hepatic clearance of CYP1A2 was 9%, occurred at ∼48 hours, and lasted for ∼1 week (Figure3b). The maximal suppression on intrinsic hepatic clearance of CYP2C9 was 17%, occurred at ∼70 hours, and lasted for ∼9 days (Figure3c).


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

Xu Y, Hijazi Y, Wolf A, Wu B, Sun YN, Zhu M - CPT Pharmacometrics Syst Pharmacol (2015)

Predicted duration and magnitude of IL-6 suppression on hepatic CLint of (a) CYP3A4, as measured by CLint of simvastatin, (b) CYP1A2, as measured by CLint of theophylline N1-demethylation, and (c) CYP2C9, as measured by CLint 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. CLint, intrinsic clearance; CYP, cytochrome P450; IL, interleukin. Percentages shown are for maximal reductions observed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592530&req=5

fig03: Predicted duration and magnitude of IL-6 suppression on hepatic CLint of (a) CYP3A4, as measured by CLint of simvastatin, (b) CYP1A2, as measured by CLint of theophylline N1-demethylation, and (c) CYP2C9, as measured by CLint 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. CLint, intrinsic clearance; CYP, cytochrome P450; IL, interleukin. Percentages shown are for maximal reductions observed.
Mentions: The established PBPK model was used to project the effect of the mean IL-6 dynamic profile on CYP450 enzymes in patients treated with blinatumomab. The changes in hepatic intrinsic clearance of CYP3A4, CYP1A2, and CYP2C9 marker substrates over time were simulated with the model. The maximal suppression on intrinsic hepatic clearance of CYP3A4 was 28%, occurred at ∼48 hours, and lasted for ∼1 week (Figure3a). Similarly, the maximal suppression on intrinsic hepatic clearance of CYP1A2 was 9%, occurred at ∼48 hours, and lasted for ∼1 week (Figure3b). The maximal suppression on intrinsic hepatic clearance of CYP2C9 was 17%, occurred at ∼70 hours, and lasted for ∼9 days (Figure3c).

Bottom Line: 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.This study shows the utility of PBPK modeling for risk assessment of cytokine-mediated drug interactions.

View Article: PubMed Central - PubMed

Affiliation: Amgen, Clinical Pharmacology, Modeling and Simulation Group, Department of Medical Sciences Thousand Oaks, California, USA.

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

No MeSH data available.


Related in: MedlinePlus