Xia Li1, Lisa Junge1, Max Taubert1, Anabelle von Georg1, Dominik Dahlinger1, Chris Starke1, Sebastian Frechen1, Christoph Stelzer2, Martina Kinzig2, Fritz Sörgel2,3, Ulrich Jaehde4, Ulrich Töx5, Tobias Goeser5, Uwe Fuhr1
1 University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany; 2 IMBP-Institute for Biomedical and Pharmaceutical Research, Nurnberg-Heroldsberg, Germany; 3 Institute of Pharmacology, West German Heart and Vascular Centre, University of Duisburg-Essen, Essen, Germany; 4 Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Germany; 5 Department of Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany.
Introduction: The extent of a drug-drug interaction (DDI) mediated by a CYP3A inhibitor is typically described by a change in the exposure of the victim drug as assessed by its AUC, i.e., by a single number. Indeed, the real extent of inhibition is highly variable during a dosing interval as it depends on the temporal course of victim and perpetrator drug concentrations at gut wall and hepatic CYP3A expression sites. Capturing the time course of inhibition is therefore difficult by using standard DDI studies; thus, a novel design was developed.
Objectives Using a novel study design, the project aimed to facilitate the characterization of the time course and extent of CYP3A inhibition at both main expression sites by more steady concentrations of perpetrator and victim drugs.
Methods: In an open-label, randomized, four-period change-over pilot study, six healthy men received continuous intraduodenal or intravenous infusions of the CYP3A substrate midazolam (MDZ) at a constant scheduled rate for 24 hours (0.26 mg/h). This was combined with intraduodenal or intravenous infusion of the CYP3A inhibitor voriconazole (VRZ), administered at scheduled rates of 7.5 mg/h and 15 mg/h from 8 to 16 and 16 to 24 hours, respectively, after the start of MDZ infusion. Concentrations of VRZ, MDZ and its major metabolites in plasma and urine were quantified by LC-MS/MS and analyzed by semi-physiological population pharmacokinetic non-linear mixed effects modelling with NONMEM 7.4.1.
Results: Previously published population pharmacokinetic models were not suitable to describe the data. Therefore, a semi-physiological model was developed, including a conventional distributional compartmental PK model with additional physiological compartments for gut lumen, gut wall, portal vein, liver, and urine. A basic version of this model was originally proposed by Frechen et al 1. In this project, the model was extended to integrate metabolites, i.e., VRZ N-oxide, as well as several metabolites of MDZ, i.e., 1’-hydroxy-MDZ (1’-OH-MDZ) and 4-hydroxy-MDZ (4-OH-MDZ) in plasma; and MDZ-glucuronide, 1’-OH-MDZ and 1’-OH-MDZ-glucuronide in urine. The metabolic fraction for each pathway was estimated based on the amount of respective metabolites excreted in the urine. The 1’-hydroxylation pathway of MDZ accounted for most of the primary metabolism of MDZ with the estimated partial metabolic fraction of 75.4%, while, the metabolic pathway of direct MDZ-glucuronidation accounted only for 0.218%.
The integration of mechanism-based inactivation on the metabolizing enzymes (maximum inactivation rate constant kinact: 2.83 h-1; dissociation rate constant KI: 9.33 µM) could describe the pharmacokinetics of VRZ well. By introducing competitive inhibition of VRZ on primary and secondary MDZ metabolism, the concentration-time profiles of MDZ and its metabolites were also captured appropriately. The estimated inhibition constant of VRZ on the metabolism of MDZ was 0.586 µM, which was similar to the inhibition constant on 4-OH-MDZ metabolism with an inhibition constant of 0.356 µM, while VRZ exhibited a weaker inhibitory effect on glucuronide conjugation of 1’-OH-MDZ with an inhibition constant of 1.13 µM.
Conclusions: The model can estimate local concentrations of substrate and inhibitor at both of the CYP3A expression sites, thus enabling to describe the temporal course of the respective extent of inhibition and to predict the exposure of CYP3A substrates when co-administered with VRZ. A combination of intravenous and intraduodenal infusions of inhibitors and substrates has the potential to provide a more accurate assessment of DDIs occurring in both gut wall and liver. Further studies with lower complexity (inhibitors without mechanism-based inhibition; single inhibitor infusion rate per study period) and larger sample sizes are required to further evaluate this approach.
Reference:
[1] Frechen S, Junge L, Saari TI, et al. A semiphysiological population pharmacokinetic model for dynamic inhibition of liver and gut wall cytochrome P450 3A by voriconazole. Clin Pharmacokinet. 2013;52(9):763-781.
Reference: PAGE () Abstr 9373 [www.page-meeting.org/?abstract=9373]
Poster: Drug/Disease Modelling - Other Topics