Florian Simon1,2, Elodie Gautier-Veyret3,4, Aurélie Truffot3, Marylore Chenel5, Léa Payen6, Françoise Stanke-Labesque3,4, Michel Tod7. 1. EA3738, Faculté de médecine de Lyon-Sud, Université de Lyon 1, 69921, Université de Lyon 1, Oullins cedex, France. fsimon.p5@gmail.com. 2. Laboratoire de biochimie-toxicologie, Centre hospitalier Lyon-Sud, Hospices civils de Lyon, Pierre Bénite, Lyon, France. fsimon.p5@gmail.com. 3. Laboratoire de Pharmacologie, Pharmacogenetique et Toxicologie, Centre Hospitalier Universitaire des Alpes, 38043, Grenoble, France. 4. University Grenoble Alpes, Inserm, CHU Grenoble Alpes, HP2, 38000, Grenoble, France. 5. Institut de recherches internationales Servier, Direction of clinical PK and pharmacometrics, Suresnes, France. 6. Laboratoire de biochimie-toxicologie, Centre hospitalier Lyon-Sud, Hospices civils de Lyon, Pierre Bénite, Lyon, France. 7. EA3738, Faculté de médecine de Lyon-Sud, Université de Lyon 1, 69921, Université de Lyon 1, Oullins cedex, France.
Abstract
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.
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.