Population In Vitro-In Vivo Correlation Model Linking Gastrointestinal Transit Time, pH, and Pharmacokinetics: Itraconazole as a Model Drug
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To establish an in vitro-in vivo correlation (IVIVC) model for Sporanox and SUBA-itraconazole formulations and to understand the impact of gastrointestinal (GI) pH and transit times on itraconazole dissolution and absorption.
IVIVC was developed based on fed/fasted pharmacokinetic data from randomized cross-over trials, in vitro dissolution studies, and prior information about typical and between subject variability of GI pH and transit times. Data were analysed using the population modelling approach as implemented in NONMEM.
Dissolution kinetics were described using first order models. The in vivo pharmacokinetics of itraconazole was described with a 2-compartment model with 4-transit absorption compartments. Pharmacokinetic profiles for fasted itraconazole periods were described based on the in vitro dissolution model, in vivo disposition model, and the prior information on GI pH and transit times. The IVIVC model indicated that drug dissolution in the fed state required an additional pH-independent dissolution pathway. The IVIVC models were presented in a ‘Shiny’ application.
An IVIVC model was established and internally evaluated for the two itraconazole formulations. The IVIVC model provides more insight into the observed variability of itraconazole pharmacokinetics and indicated that GI pH and transit times influence in vivo dissolution and exposure.
KEY WORDSin vitro- in vivo correlation itraconazole NONMEM population pharmacokinetic
Akaike information criteria
Area under the concentration-time curve
Biopharmaceutics classification system
Gastrointestinal transit time
High performance liquid chromatography
In vitro-in vivo correlation
Minimum objective function value
Model event time
Non-linear mixed effect modelling
Visual predictive check
ACKNOWLEDGMENTS AND DISCLOSURES
All the pharmacokinetic studies used in the analysis were sponsored by Mayne Pharma International. S.M and D.H are employees at Mayne Pharma. R.U. has acted as a paid consultant for Mayne Pharma International. The Australian Centre for Pharmacometrics is an initiative of the Australian Government as part of the National Collaborative Research Infrastructure Strategy. A.Y.A is a PhD student receiving an Endeavour Scholarship funded by the Department of Education and Training of the Australian Government (Scholarship ID no. 4088).
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