Pharmaceutical Research

, Volume 33, Issue 7, pp 1782–1794 | Cite as

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

  • Ahmad Y. Abuhelwa
  • Stuart Mudge
  • David Hayes
  • Richard N. Upton
  • David J. R. Foster
Research Paper



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.


in vitro- in vivo correlation itraconazole NONMEM population pharmacokinetic 



Akaike information criteria


Area under the concentration-time curve


Biopharmaceutics classification system


Maximum concentration




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



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).

Supplementary material

11095_2016_1917_MOESM1_ESM.pdf (47 kb)
ESM 1 (PDF 47 kb)


  1. 1.
    Boogaerts M, Maertens J. Clinical experience with itraconazole in systemic fungal infections. Drugs. 2001;61(1):39–47.CrossRefPubMedGoogle Scholar
  2. 2.
    De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs. 2001;61(1):27–37.CrossRefPubMedGoogle Scholar
  3. 3.
    Peeters J, Neeskens P, Tollenaere JP, Van Remoortere P, Brewster ME. Characterization of the interaction of 2‐hydroxypropyl‐β‐cyclodextrin with itraconazole at pH 2, 4, and 7. J Pharm Sci. 2002;91(6):1414–22.CrossRefPubMedGoogle Scholar
  4. 4.
    Poirier J-M, Cheymol G. Optimisation of itraconazole therapy using target drug concentrations. Clin Pharmacokinet. 1998;35(6):461–73.CrossRefPubMedGoogle Scholar
  5. 5.
    Abuhelwa AY, Foster DJ, Mudge S, Hayes D, Upton RN. Population pharmacokinetic modelling of itraconazole and hydroxyl-itraconazole for oral SUBA-itraconazole and Sporanox capsule formulations in healthy subjects in fed and fasted states. Antimicrob Agents Chemother. 2015.Google Scholar
  6. 6.
    Yun H-y, Baek MS, Park IS, Choi BK, Kwon K-i. Comparative analysis of the effects of rice and bread meals on bioavailability of itraconazole using NONMEM in healthy volunteers. Eur J Clin Pharmacol. 2006;62(12):1033–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Jaruratanasirikul S, Kleepkaew A. Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole. Eur J Clin Pharmacol. 1997;52(3):235–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Smith D, Velde V, Woestenborghs R, Gazzard B. The pharmacokinetics of oral itraconazole in AIDS patients. J Pharm Pharmacol. 1992;44(7):618–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Janssen Pharmaceuticals Inc. Sporanox (itraconazole) capsules. Janssen Pharmaceuticals Inc, Beers, Belgium.Google Scholar
  10. 10.
    Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides, part V. (1989–2009). Ellicott City: Icon Development Solutions; 2009.Google Scholar
  11. 11.
    R Core Team. R: a language and environment for statistical computing Vienna, Austria R Foundation for Statistical Computing; 2014.Google Scholar
  12. 12.
    Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer; 2009.CrossRefGoogle Scholar
  13. 13.
    Wickham H. plyr—the split-apply-combine strategy for data analysis. J Stat Softw. 2011;40(1):1–29.CrossRefGoogle Scholar
  14. 14.
    Wickham H. Scales: Scale functions for graphics:; 2014.Google Scholar
  15. 15.
    Ludden TM, Beal SL, Sheiner LB. Comparison of the Akaike Information Criterion, the Schwarz criterion and the F test as guides to model selection. J Pharmacokinet Biopharm. 1994;22(5):431–45.CrossRefPubMedGoogle Scholar
  16. 16.
    Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2013;2, e38.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wagner JG. Interpretation of percent dissolved‐time plots derived from in vitro testing of conventional tablets and capsules. J Pharm Sci. 1969;58(10):1253–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Higuchi T. Mechanism of sustained‐action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52(12):1145–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Hixson A, Crowell J. Dependence of reaction velocity upon surface and agitation. Ind Eng Chem. 1931;23(10):1160–8.CrossRefGoogle Scholar
  20. 20.
    Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15(1):25–35.CrossRefGoogle Scholar
  21. 21.
    Simonian HP, Vo L, Doma S, Fisher RS, Parkman HP. Regional postprandial differences in pH within the stomach and gastroesophageal junction. Dig Dis Sci. 2005;50(12):2276–85.CrossRefPubMedGoogle Scholar
  22. 22.
    Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut. 1988;29(8):1035–41.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    McCloy R, Greenberg G, Baron J. Duodenal pH in health and duodenal ulcer disease: effect of a meal, Coca-Cola, smoking, and cimetidine. Gut. 1984;25(4):386–92.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ewe K, Press AG, Bollen S, Schuhn I. Gastric emptying of indigestible tablets in relation to composition and time of ingestion of meals studied by metal detector. Dig Dis Sci. 1991;36(2):146–52.CrossRefPubMedGoogle Scholar
  25. 25.
    Davis S, Hardy J, Fara J. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986;27(8):886–92.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    RStudio Inc. Shiny: web application framework for R. R package version 0.10.1.
  27. 27.
    Abuhelwa AY, Foster DJ, Upton RN. ADVAN-style analytical solutions for common pharmacokinetic models. J Pharmacol Toxicol Methods. 2015;73:42–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Mooney K, Mintun M, Himmelstein K, Stella V. Dissolution kinetics of carboxylic acids II: effect of buffers. J Pharm Sci. 1981;70(1):22–32.CrossRefPubMedGoogle Scholar
  29. 29.
    Lange D, Pavao JH, Wu J, Klausner M. Effect of a cola beverage on the bioavailability of itraconazole in the presence of H2 blockers. J Clin Pharmacol. 1997;37(6):535–40.CrossRefPubMedGoogle Scholar
  30. 30.
    Clarke G, Newton J, Short M. Gastrointestinal transit of pellets of differing size and density. Int J Pharm. 1993;100(1):81–92.CrossRefGoogle Scholar
  31. 31.
    Devereux J, Newton J, Short M. The influence of density on the gastrointestinal transit of pellets. J Pharm Pharmacol. 1990;42(7):500–1.CrossRefPubMedGoogle Scholar
  32. 32.
    Abrahamsson B, Alpsten M, Jonsson UE, Lundberg P, Sandberg A, Sundgren M, et al. Gastro-intestinal transit of a multiple-unit formulation (metoprolol CR/ZOK) and a non-disintegrating tablet with the emphasis on colon. Int J Pharm. 1996;140(2):229–35.CrossRefGoogle Scholar
  33. 33.
    Charman WN, Porter CJ, Mithani S, Dressman JB. Physicochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci. 1997;86(3):269–82.CrossRefPubMedGoogle Scholar
  34. 34.
    Food and Drug Administration. Guidance for industry: extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations. Center for Drug Evaluation and Research, Rockville. 1997.Google Scholar
  35. 35.
    Mayne Pharma International Pty Ltd. Lozanoc® (Itraconazole) 50 mg capsules: consumer medicine information. Available from:
  36. 36.
    Banka S, Ryan K, Thomson W, Newman WG. Pernicious anemia—genetic insights. Autoimmun Rev. 2011;10(8):455–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Lake-Bakaar G, Quadros E, Beidas S, Elsakr M, Tom W, Wilson DE, et al. Gastric secretory failure in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1988;109(6):502–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Lu PJ, Hsu PI, Chen CH, Hsiao M, Chang WC, Tseng HH, et al. Gastric juice acidity in upper gastrointestinal diseases. World J Gastroenterol. 16(43):5496–501.Google Scholar
  39. 39.
    Weitschies W, Blume H, Mönnikes H. Magnetic marker monitoring: high resolution real-time tracking of oral solid dosage forms in the gastrointestinal tract. Eur J Pharm Biopharm. 2010;74(1):93–101.CrossRefPubMedGoogle Scholar
  40. 40.
    Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev. 2001;50:S41–67.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ahmad Y. Abuhelwa
    • 1
  • Stuart Mudge
    • 2
  • David Hayes
    • 2
  • Richard N. Upton
    • 1
  • David J. R. Foster
    • 1
  1. 1.Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
  2. 2.Mayne Pharma InternationalAdelaideAustralia

Personalised recommendations