A Novel Study Design Using Continuous Intravenous and Intraduodenal Infusions of Midazolam and Voriconazole for Mechanistic Quantitative Assessment of Hepatic and Intestinal CYP3A Inhibition
| Autor: | Max Taubert, Lisa Junge, Tobias Goeser, Christoph Stelzer, Anabelle von Georg, Sebastian Frechen, Chris Starke, Uwe Fuhr, Ulrich Jaehde, Xia Li, Ulrich Töx, Fritz Sörgel, Martina Kinzig, Dominik Dahlinger |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Duodenum CYP3A Midazolam Population Medizin Pilot Projects Pharmacology Models Biological 030226 pharmacology & pharmacy 03 medical and health sciences 0302 clinical medicine Non-competitive inhibition Pharmacokinetics medicine Cytochrome P-450 CYP3A Humans Computer Simulation Drug Interactions Infusions Parenteral Pharmacology (medical) Infusions Intravenous education Biotransformation education.field_of_study biology Chemistry Area under the curve Cytochrome P450 Metabolism Healthy Volunteers Intestines Anti-Anxiety Agents Liver 030220 oncology & carcinogenesis biology.protein Cytochrome P-450 CYP3A Inhibitors Voriconazole medicine.drug |
| Popis: | The extent of a drug-drug interaction (DDI) mediated by cytochrome P450 (CYP) 3A inhibitors is highly variable during a dosing interval, as it depends on the temporal course of victim and perpetrator drug concentrations at intestinal and hepatic CYP3A expression sites. Capturing the time course of inhibition is therefore difficult using standard DDI studies assessing changes in area under the curve; thus, a novel design was developed. In a 4-period changeover pilot study, 6 healthy men received intraduodenal or intravenous infusions of the CYP3A substrate midazolam (MDZ) at a rate of 0.26 mg/h for 24 hours. This was combined with intraduodenal or intravenous infusion of the CYP3A inhibitor voriconazole (VRZ), administered at rates of 7.5 mg/h from 8 to 16 hours and of 15 mg/h from 16 to 24 hours, after starting midazolam administration. Plasma and urine concentrations of VRZ, MDZ, and its major metabolites were quantified by liquid chromatography-tandem mass spectrometry and analyzed by semiphysiological population pharmacokinetic nonlinear mixed-effects modeling. A model including mechanism-based inactivation of the metabolizing enzymes (maximum inactivation rate constant kinₐct, 2.83 h−¹; dissociation rate constant (Formula presented.), 9.33 μM) described the pharmacokinetics of VRZ well. By introducing competitive inhibition by VRZ on primary and secondary MDZ metabolism, concentration-time profiles, MDZ and its metabolites were captured appropriately. The model provides estimates of local concentrations of substrate and inhibitor at the major CYP3A expression sites and thus of the respective dynamic extent of inhibition. 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. |
| Databáze: | OpenAIRE |
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