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Population In Vitro-In Vivo Correlation Model Linking Gastrointestinal Transit Time, pH, and Pharmacokinetics: Itraconazole as a Model Drug

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Abbreviations

AIC:

Akaike information criteria

AUC:

Area under the concentration-time curve

BCS:

Biopharmaceutics classification system

Cmax :

Maximum concentration

GI:

Gastrointestinal

GITT:

Gastrointestinal transit time

HPLC:

High performance liquid chromatography

IVIVC:

In vitro-in vivo correlation

MOFV:

Minimum objective function value

MTIME:

Model event time

NONMEM:

Non-linear mixed effect modelling

VPC:

Visual predictive check

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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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Authors and Affiliations

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

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

  2. Mayne Pharma International, Adelaide, South Australia, Australia

    Stuart Mudge & David Hayes

Authors
  1. Ahmad Y. Abuhelwa
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  2. Stuart Mudge
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  3. David Hayes
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  5. David J. R. Foster
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Correspondence to Ahmad Y. Abuhelwa.

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Abuhelwa, A.Y., Mudge, S., Hayes, D. et al. Population In Vitro-In Vivo Correlation Model Linking Gastrointestinal Transit Time, pH, and Pharmacokinetics: Itraconazole as a Model Drug. Pharm Res 33, 1782–1794 (2016). https://doi.org/10.1007/s11095-016-1917-1

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  • DOI: https://doi.org/10.1007/s11095-016-1917-1

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