A Novel Study Design Using Continuous Intravenous and Intraduodenal Infusions of Midazolam and Voriconazole for Mechanistic Quantitative Assessment of Hepatic and Intestinal CYP3A Inhibition.
Adult
Anti-Anxiety Agents
/ administration & dosage
Biotransformation
/ drug effects
Computer Simulation
Cytochrome P-450 CYP3A
/ drug effects
Cytochrome P-450 CYP3A Inhibitors
/ administration & dosage
Drug Interactions
Duodenum
Healthy Volunteers
Humans
Infusions, Intravenous
Infusions, Parenteral
Intestines
/ drug effects
Liver
/ drug effects
Male
Midazolam
/ administration & dosage
Models, Biological
Pilot Projects
Voriconazole
/ administration & dosage
CYP3A
drug-drug interaction
midazolam
semiphysiological population pharmacokinetic modeling
voriconazole
Journal
Journal of clinical pharmacology
ISSN: 1552-4604
Titre abrégé: J Clin Pharmacol
Pays: England
ID NLM: 0366372
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
31
01
2020
accepted:
24
03
2020
pubmed:
20
5
2020
medline:
1
7
2021
entrez:
20
5
2020
Statut:
ppublish
Résumé
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 k
Substances chimiques
Anti-Anxiety Agents
0
Cytochrome P-450 CYP3A Inhibitors
0
CYP3A protein, human
EC 1.14.14.1
Cytochrome P-450 CYP3A
EC 1.14.14.1
Voriconazole
JFU09I87TR
Midazolam
R60L0SM5BC
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1237-1253Informations de copyright
© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.
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