A Semiphysiological Population Pharmacokinetic Model for Dynamic Inhibition of Liver and Gut Wall Cytochrome P450 3A by Voriconazole

Abstract

The proposed semiphysiological modelling approach generated a mechanistic description of the complex DDI occurring at major CYP3A expression sites and thus may serve as a powerful tool to maximise information acquired from clinical DDI studies. The model has been shown to draw precise and accurate predictions. Therefore, simulations based on this kind of models may be used for various clinical scenarios to improve pharmacotherapy.

Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1‐OH‐midazolam in morbidly obese and weight loss surgery patients

“…The structural semi‐PBPK model was adopted from Yang et al . (2003) and Frechen et al . (2013) and consisted of a compartment representing the gut wall, the portal vein, and the liver, and an empirical compartment model for midazolam and 1‐OH midazolam, representing the rest of the body.…”

“…To fully characterize the influence of weight loss surgery on CYP3A‐mediated drug metabolism in both the gut wall and the liver, a semiphysiologically based pharmacokinetic (semi‐PBPK) model taking into account these distinct processes needs to be applied to both midazolam and the CYP3A‐mediated metabolite 1‐OH‐midazolam concentrations obtained after oral and i.v. administration in these populations . Such a semi‐PBPK model consists of a compartment representing the gut wall, the portal vein, and the liver, and an empirical compartment model for midazolam and 1‐OH‐midazolam, representing the rest of the body.…”

Semimechanistic Population Pharmacokinetic Model to Predict the Drug–Drug Interaction Between S‐ketamine and Ticlopidine in Healthy Human Volunteers

“…Three‐compartment mammillary model and a two‐compartment model were successfully linked to physiological compartments representing the gut wall, portal vein, and liver for S ‐ketamine and norketamine, respectively. A semimechanistic model for ticlopidine pharmacokinetics that included four transit compartments, and a two‐compartment distributional model in conjunction with the gut wall, portal vein, and liver compartments was built following the modeling strategy described earlier24 and added to the S ‐ketamine/norketamine model. Finally, S ‐ketamine and ticlopidine models were linked together with MSM describing the mechanism‐based inhibition of S ‐ketamine metabolism by ticlopidine.…”

“…For all three substances, we commenced with a simple empirical one‐compartment model, and nested models were developed in a stepwise manner. The optimum number of compartments to account for drug disposition kinetics was optimized at first, after which the physiological compartments for gut wall, portal vein, and liver were added to the structural model 24, 25. Physiological parameters incorporated into the model were obtained from the previously published studies ( Table 1).…”

Pharmacogenomics of Antifungal Agents

“…CYP2C9 also plays a minor role in voriconazole metabolism [21]. Voriconazole has recently been found to inhibit UGT2B [130], although the significance of this is unclear. In addition to CYP-mediated metabolism of voriconazole, which makes up 75% of the metabolic pathway, 25% of voriconazole metabolism is mediated by the FMO enzymes [129].…”