AAPS PharmSciTech

, Volume 14, Issue 3, pp 1244–1254 | Cite as

In VitroIn Vivo Correlation of Efavirenz Tablets Using GastroPlus®

  • Thiago da Silva Honório
  • Eduardo Costa Pinto
  • Helvécio Vinicius A. Rocha
  • Valeria Sant’Anna Dantas Esteves
  • Tereza Cristina dos Santos
  • Helena Carla Rangel Castro
  • Carlos Rangel Rodrigues
  • Valeria Pereira de Sousa
  • Lucio Mendes Cabral
Research Article


The aim of the present work was to use GastroPlus™ software for the prediction of pharmacokinetic profiles and in vitroin vivo correlation (IVIVC) as tools to optimize the development of new generic medications. GastroPlus™ was used to simulate the gastrointestinal compartment and was based on the advanced compartmental absorption and transit model. Powder dissolution and efavirenz tablet dissolution studies were carried out to generate data from which correlation was established. The simulated plasma profile, based on the physicochemical properties of efavirenz, was almost identical to that observed in vivo for biobatches A and B. A level A IVIVC was established for the dissolution method obtained for the generic candidate using the Wagner–Nelson (r 2 = 0.85) and for Loo–Riegelman models (r 2 = 0.92). The percentage of fraction absorbed indicated that 0.5% sodium lauryl sulfate may be considered a biorelevant dissolution medium for efavirenz tablets. The simulation of gastrointestinal bioavailability and IVIVC obtained from immediate-release tablet formulations suggests that GastroPlus™ is a valuable in silico method for IVIVC and for studies directed at developing formulations of class II drugs.


bioavailability computational simulation efavirenz GastroPlus™ in vivo–in vitro correlation 



This work was supported by FAPERJ, Edital CAPES Nanobiotecnologia 2008, and CNPq. We are grateful to Michelle Parvatiyar for her English review.


  1. 1.
    Food and Drug Administration. Guidance for industry: bioavailability and bioequivalence studies for orally administers drug products. General Considerations. US Department of Health and Human Services, CDER/FDA; 2003.Google Scholar
  2. 2.
    Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a Biopharmaceutic Drug Classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pham Res. 1995;12:413–20.CrossRefGoogle Scholar
  3. 3.
    Food and Drug Administration. Guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System. US Department of Health and Human Services, CDER/FDA; 2000.Google Scholar
  4. 4.
    Yu LX, Amidon GL, Polli JE, Zhao H, Mehta MU, Conner DP, et al. Biopharmaceutics Classification System: the scientific basis for biowaiver extensions. Pharm Res. 2002;19:921–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Tubic-Grozdanis M, Bolger MB, Langguth P. Application of gastrointestinal simulation for extensions for biowaivers of highly permeable compounds. AAPS J. 2008;10:213–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Tsume Y, Amidon GL. The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class II immediate-release drugs predicted by computer simulation. Mol Pharm. 2010;7:1235–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Rinak E, Dokoumetzidis A, Valsami G, Macheras P. Identification of biowaivers among class II drugs: theoretical justification and practical examples. Pharm Res. 2004;21:1567–72.CrossRefGoogle Scholar
  8. 8.
    Polli JE, Yu LX, Cook JA, Amidon GL, Borchardt RT, Burnside BA, et al. Summary workshop report: Biopharmaceutics Classification System—implementation challenges and extension opportunities. J Pharm Sci. 2004;93:1375–81.PubMedCrossRefGoogle Scholar
  9. 9.
    Pelkonen O, Turpeinen M, Raunio H. In vivo-in vitro-in silico pharmacokinetic modelling in drug development. Clin Pharmacokinet. 2011;50:483–91.PubMedCrossRefGoogle Scholar
  10. 10.
    Grbic S, Parojcic J, Ibric S, Djuric Z. In vitro-in vivo correlation for glicazide immediate-release tablets based on mechanistic absorption simulation. AAPS PharmSciTech. 2011;12:165–71.PubMedCrossRefGoogle Scholar
  11. 11.
    Simulations Plus, Manual GastroPlus™, California, EUA; 2010.Google Scholar
  12. 12.
    Wei H, Löbenberg R. Biorelevant dissolution media as predictive tool for glyburide a class II drug. Eur J Pharm Sci. 2006;29:45–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Okumu A, Dimaso M, Löbenberg R. Computer simulations using GastroPlus™ to justify a biowaiver for etoricoxib solid oral drug products. Eur J Pharm Biopham. 2009;72:91–8.CrossRefGoogle Scholar
  14. 14.
    Kovacevic I, Parojeie J, Homsek I, Tubie-Grozdanis M, Langguth P. Justification of biowaiver for carbamazepine, a low soluble high permeable compound, in solid dosage forms based on IVIVC and gastrointestinal simulation. Mol Pharm. 2009;6:40–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Okumu A, DiMaso M, Löbenberg R. Dynamic dissolution testing to establish in vitro/in vivo correlations for montelukast sodium, a poorly soluble drug. Pharm Res. 2008;25:2778–85.PubMedCrossRefGoogle Scholar
  16. 16.
    Maggiolo F. Efavirenz: a decade of clinical experience in the treatment of HIV. J Antimicrob Chemother. 2009;64:910–28.PubMedCrossRefGoogle Scholar
  17. 17.
    Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennerna H, Hussain AS, et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm. 2004;1:85–96.PubMedCrossRefGoogle Scholar
  18. 18.
    Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the world model list of essential medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm. 2004;58:265–78.PubMedCrossRefGoogle Scholar
  19. 19.
    Müller CE. Prodrug approaches for enhancing the bioavailability of drugs with low solubility. Chem Biodivers. 2009;6:2071–83.PubMedCrossRefGoogle Scholar
  20. 20.
    International Standard Organization. General requirements for the competence of the material producers. ISO Guide 34, 2009.Google Scholar
  21. 21.
    The United States Pharmacopoeia and National Formulary. 34th ed. Rockville, MD: USP Convention Inc.; 2011.Google Scholar
  22. 22.
    ICH, validation of analytical procedures: text and methodology (Q2R1), in International Conference on Harmonization; November 2005.Google Scholar
  23. 23.
    Azarmi S, Roa W, Löbenberg R. Current perspectives in dissolution testing of conventional and novel dosage forms. Int J Pharm. 2007;328:12–21.PubMedCrossRefGoogle Scholar
  24. 24.
    Brazilian Pharmacopoeia. 5th ed. Brazilian Health Surveillance Agency; 2010.Google Scholar
  25. 25.
    Lu ATK, Frisella ME, Johnson KC. Dissolution modeling: factors affecting the dissolution rates of polydisperse powders. Pharm Res. 1993;10:1308–14.PubMedCrossRefGoogle Scholar
  26. 26.
    Mithani SD, Bakatselou V, TenHoor CN, Dressman JB. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharm Res. 1996;10:164–7.Google Scholar
  27. 27.
    Mahapatra S, Thakur TS, Joseph S, Varughese S, Desiraju GR. New solid state forms of the anti-HIV drug efavirenz. Conformational flexibility and Z' issues. Cryst Growth Des. 2010;10:3191–202.CrossRefGoogle Scholar
  28. 28.
    Kesisoglou F, Wu Y. Understanding the effect of API properties on bioavailability through absorption modeling. AAPS J. 2008;10:516–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Desai D, Rinaldi F, Kothari S, Paruchuri S, Li D, Lai M, et al. Effect of hydroxypropyl cellulose (HPC) on dissolution rate of hydrochlorothiazide tablets. Int J Pharm. 2006;308:40–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Gorman EA, Rhodes CT, Rudnic EM. An evaluation of croscarmellose as a tablet disintegrant in direct compression systems. Drug Dev Ind Pharm. 1982;8:397–410.CrossRefGoogle Scholar
  31. 31.
    Rowel RC, Sheskey PJ, Quinn ME. Handbook of pharmaceutical excipients. 6th ed. London: Pharmaceutical Press; 2009.Google Scholar
  32. 32.
    Brown CK, Chokshi HP, Nickerson B, Reed RA, Rohrs BR, Shah PS. Acceptable analytical practices for dissolution testing of poorly soluble compounds. Pharm Technol. 2004;28:56–65.Google Scholar
  33. 33.
    Takano R, Furumoto K, Shiraki K, Takata N, Hayashi Y, Aso Y, et al. Rate-limiting steps for oral absorption for poorly water-soluble drugs in dogs; prediction from miniscale dissolution test and a physiologically-based computer simulation. Pharm Res. 2008;25:2334–44.PubMedCrossRefGoogle Scholar
  34. 34.
    Takano R, Sugano K, Higashida A, Hayashi Y, Machida M, Aso Y, et al. Oral absorption of poorly water-soluble drugs: computer simulation of fraction absorbed in humans from miniscale dissolution test. Pharm Res. 2006;23:1144–56.PubMedCrossRefGoogle Scholar
  35. 35.
    He Z, Zhong D, Chen X, Liu X, Tang X, Zhao L. Development of medium for nimodipine tablets based on bioavailability evaluation. Eur J Pharm Sci. 2004;21:487–91.PubMedCrossRefGoogle Scholar
  36. 36.
    Pabla D, Akhlaghi F, Zia H. A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively couple plasma mass spectrometry. Eur J Pharm Biopharm. 2009;72:105–10.PubMedCrossRefGoogle Scholar
  37. 37.
    Rekić D, Röshammar D, Mukonzo J, Ashton M. In silico prediction of efavirenz and rifampicin drug-drug interaction considering weight and CYP 2B6 phenotype. Br J Clin Pharmacol. 2011;71:536–43.PubMedCrossRefGoogle Scholar
  38. 38.
    Nanzigu S, Eriksen J, Makumbi F, Lanke S, Mahindi M, Kiguba R, et al. Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV-infected Ugandans. HIV Med. 2012;13:193–201.PubMedGoogle Scholar
  39. 39.
    Villani P, Regazzi MB, Castelli F, Viale P, Torti C, Seminari E, et al. Pharmacokinetics of efavirenz (EFV) alone and in combination therapy with nelfinavir (NFV) in HIV-I infected patients. Br J Clin Pharmacol. 1999;48:712–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Cristofoletti R, Nair A, Abrahamsson B, Groot DW, Kopp S, Langguth P, et al. Biowaiver monographs for immediate release solid oral dosage forms: efavirenz. J Pharm Sci. 2013;102:318–29.PubMedCrossRefGoogle Scholar
  41. 41.
    DiCenzo R, Forrest A, Squires KE, Hammer SM, Fischl MA, Wu H, et al. Indinavir, efavirenz, and abacavir pharmacokinetics in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. 2003;47:1929–35.PubMedCrossRefGoogle Scholar
  42. 42.
    Pfister M, Labbé L, Hammer SM, Mellors J, Bennett KK, Rosenkranz S, et al. Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: adult AIDS clinical trial group study 398. Antimicrob Agents Chemother. 2003;47:130–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Kocic I, Homseka I, Dacevic M, Grbic S, Parojcic J, Vucicevic K, et al. A case study on the in silico absorption simulations of levothyroxine sodium immediate-release tablets. Biopharm Drug Dispos. 2012;33:146–59.PubMedCrossRefGoogle Scholar
  44. 44.
    Wei H, Dalton C, Di Maso M, Kanfer I, Löbenberg R. Physicochemical characterization of five glyburide powders: a BCS based approach to predict oral absorption. Eur J Pharm Biopharm. 2008;69:1046–56.PubMedCrossRefGoogle Scholar
  45. 45.
    Jantratid E, Prakongpan S, Amidon GL, Dressman JB. Feasibility of biowaiver extension to biopharmaceutics classification system class III drug products cimetidine. Clin Pharmacokinet. 2006;45:385–99.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  • Thiago da Silva Honório
    • 1
  • Eduardo Costa Pinto
    • 1
  • Helvécio Vinicius A. Rocha
    • 2
  • Valeria Sant’Anna Dantas Esteves
    • 2
  • Tereza Cristina dos Santos
    • 2
  • Helena Carla Rangel Castro
    • 3
  • Carlos Rangel Rodrigues
    • 1
  • Valeria Pereira de Sousa
    • 1
  • Lucio Mendes Cabral
    • 1
  1. 1.Faculty of PharmacyFederal University of Rio de JaneiroRio de JaneiroBrazil
  2. 2.Research and Innovation, Farmanguinhos Official Pharmaceutical LaboratoryOswaldo Cruz FoundationRio de JaneiroBrazil
  3. 3.Institute of BiologyFluminense Federal UniversityNiteróiBrazil

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