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Population in vitro–in vivo pharmacokinetic model of first-pass metabolism: itraconazole and hydroxy-itraconazole

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Abstract

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.

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Acknowledgements

A.Y.A is a Research Fellow at the School of Pharmacy and Medical Sciences at the University of South Australia supported by a Science and Industry Endowment Fund STEM + Business Fellowship of the Commonwealth Scientific and Industrial Research Organisation. All the pharmacokinetic studies used in the analysis were sponsored by Mayne Pharma International. S.M is an employee at Mayne Pharma. D.J.R.F, R.N.U and A.Y.A have acted as paid consultants 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.

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Authors and Affiliations

  1. Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia

    Ahmad Y. Abuhelwa, Richard N. Upton & David J. R. Foster

  2. Mayne Pharma International, Salisbury South, SA, Australia

    Stuart Mudge

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  1. Ahmad Y. Abuhelwa
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  2. Stuart Mudge
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Correspondence to Ahmad Y. Abuhelwa.

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Abuhelwa, A.Y., Mudge, S., Upton, R.N. et al. Population in vitro–in vivo pharmacokinetic model of first-pass metabolism: itraconazole and hydroxy-itraconazole. J Pharmacokinet Pharmacodyn 45, 181–197 (2018). https://doi.org/10.1007/s10928-017-9555-8

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  • DOI: https://doi.org/10.1007/s10928-017-9555-8

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