Population in vitro–in vivo pharmacokinetic model of first-pass metabolism: itraconazole and hydroxy-itraconazole
| Autor: | Richard N. Upton, Stuart Mudge, Ahmad Y. Abuhelwa, David J. R. Foster |
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| Přispěvatelé: | Abuhelwa, Ahmad Y, Mudge, Stuart, Upton, Richard N, Foster, David JR |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Antifungal Agents mixed-inhibition Itraconazole 030106 microbiology Population Administration Oral first-pass metabolism Absorption (skin) Pharmacology Models Biological 030226 pharmacology & pharmacy Young Adult 03 medical and health sciences First pass effect 0302 clinical medicine Pharmacokinetics in vitro–in vivo correlation In vivo medicine Humans Distribution (pharmacology) Gastrointestinal Transit education education.field_of_study Chemistry gastrointestinal pH Hydrogen-Ion Concentration itraconazole NONMEM Gastrointestinal Tract Kinetics population pharmacokinetic medicine.drug |
| Zdroj: | Journal of Pharmacokinetics and Pharmacodynamics. 45:181-197 |
| ISSN: | 1573-8744 1567-567X |
| Popis: | The aim of this study was to develop a population in vitro–in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit time and in vitro dissolution models of ICZ with the absorption and disposition kinetics of ICZ and HICZ. Mean concentration intravenous data, and single- and multi-dose oral data were used for model development. Model development was conducted in NONMEM in a stepwise manner. First, a model of intravenous data (systemic kinetics) was established and then extended to include the oral data. The latter was then extended to establish the in vitro–in vivo pharmacokinetic model. The systemic disposition of ICZ was best described by a 3-compartment model with oral absorption described by 4-transit compartments and HICZ distribution by a 1-compartment model. ICZ clearance was best described using a mixed inhibition model that allowed HICZ concentrations to inhibit the clearance of parent drug. HICZ clearance was described by Michaelis–Menten elimination kinetics. An in vitro–in vivo model was successfully established for both formulations. The presented model was able to describe ICZ and HICZ plasma concentrations over a wide range of oral and intravenous doses and allowed the exploration of complexities associated with the non-linear ICZ and HICZ kinetics. The model may provide insight into the variability in exposure of ICZ with respect to relating in vivo dissolution characteristics with in vivo disposition kinetics. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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