Modeling Approach to Predict the Impact of Inflammation on the Pharmacokinetics of CYP2C19 and CYP3A4 Substrates

Purpose For decades, inflammation has been considered a cause of pharmacokinetic variability, mainly in relation to the inhibitory effect of pro-inflammatory cytokines on the expression level and activity of cytochrome P450 (CYP). In vitro and clinical studies have shown that two major CYPs, CYP2C19...

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Bibliographic Details
Published in:Pharmaceutical research 2021-03, Vol.38 (3), p.415-428
Main Authors: Simon, Florian, Gautier-Veyret, Elodie, Truffot, Aurélie, Chenel, Marylore, Payen, Léa, Stanke-Labesque, Françoise, Tod, Michel
Format: Article
Language:English
Subjects:
Analysis
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
C-reactive protein
Cytochrome P450
Cytokines
Inflammation
Life Sciences
Medical Law
Medical research
Medicine, Experimental
Midazolam
Omeprazole
Pharmacokinetics
Pharmacology/Toxicology
Pharmacy
Research Paper
Voriconazole
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Summary:Purpose For decades, inflammation has been considered a cause of pharmacokinetic variability, mainly in relation to the inhibitory effect of pro-inflammatory cytokines on the expression level and activity of cytochrome P450 (CYP). In vitro and clinical studies have shown that two major CYPs, CYP2C19 and CYP3A4, are both impaired. The objective of the present study was to quantify the impact of the inflammatory response on the activity of both CYPs in order to predict the pharmacokinetic profile of their substrates according to systemic C-reactive protein (CRP). Methods The relationships between CRP concentration and both CYPs activities were estimated and validated using clinical data first on midazolam then on voriconazole. Finally, clinical data on omeprazole were used to validate the findings. For each substrate, a physiologically based pharmacokinetics model was built using a bottom-up approach, and the relationships between CRP level and CYP activities were estimated by a top-down approach. After incorporating the respective relationships, we compared the predictions and observed drug concentrations. Results Changes in pharmacokinetic profiles and parameters induced by inflammation seem to be captured accurately by the models. Conclusions These findings suggest that the pharmacokinetics of CYP2C19 and CYP3A4 substrates can be predicted depending on the CRP concentration.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-021-03019-7