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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 time course of IL-6 suppression on CLint of CYP3A4 at constant IL-6 concentrations (50, 100, and 500 pg/mL) for 3 weeks, as measured by CLint of simvastatin. CLint, intrinsic clearance; CYP, cytochrome P450; IL, interleukin.
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fig04: Predicted time course of IL-6 suppression on CLint of CYP3A4 at constant IL-6 concentrations (50, 100, and 500 pg/mL) for 3 weeks, as measured by CLint of simvastatin. CLint, intrinsic clearance; CYP, cytochrome P450; IL, interleukin.

Mentions: The PBPK model was used to evaluate the effect of duration of suppression on hepatic intrinsic clearance of CYP3A4. With constant IL-6 concentrations of 50, 100, and 500 pg/mL, which mimic conditions of chronic inflammation, the time to reach maximal suppression (i.e., steady state) on CYP3A4 activity could take >2 weeks. The magnitude of suppression depends on IL-6 concentration and duration of suppression (Figure4). For instance, with a constant IL-6 concentration of 50 pg/mL over 3 weeks, the suppression on the hepatic intrinsic clearance of CYP3A4 is ∼17% by day 2 but 33% by week 3. This finding indicates that the duration of IL-6 elevation is a critical factor in determining the magnitude of CYP450 suppression. Given the transient nature of blinatumomab-induced cytokine elevation,5 its impact on exposures to CYP450 substrates is predicted to be limited.


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 time course of IL-6 suppression on CLint of CYP3A4 at constant IL-6 concentrations (50, 100, and 500 pg/mL) for 3 weeks, as measured by CLint of simvastatin. CLint, intrinsic clearance; CYP, cytochrome P450; IL, interleukin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Predicted time course of IL-6 suppression on CLint of CYP3A4 at constant IL-6 concentrations (50, 100, and 500 pg/mL) for 3 weeks, as measured by CLint of simvastatin. CLint, intrinsic clearance; CYP, cytochrome P450; IL, interleukin.
Mentions: The PBPK model was used to evaluate the effect of duration of suppression on hepatic intrinsic clearance of CYP3A4. With constant IL-6 concentrations of 50, 100, and 500 pg/mL, which mimic conditions of chronic inflammation, the time to reach maximal suppression (i.e., steady state) on CYP3A4 activity could take >2 weeks. The magnitude of suppression depends on IL-6 concentration and duration of suppression (Figure4). For instance, with a constant IL-6 concentration of 50 pg/mL over 3 weeks, the suppression on the hepatic intrinsic clearance of CYP3A4 is ∼17% by day 2 but 33% by week 3. This finding indicates that the duration of IL-6 elevation is a critical factor in determining the magnitude of CYP450 suppression. Given the transient nature of blinatumomab-induced cytokine elevation,5 its impact on exposures to CYP450 substrates is predicted to be limited.

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