Skip to main content

Application of Mechanistic Ocular Absorption Modeling and Simulation to Understand the Impact of Formulation Properties on Ophthalmic Bioavailability in Rabbits: a Case Study Using Dexamethasone Suspension

Abstract

Developing mathematical models to predict changes in ocular bioavailability and pharmacokinetics due to differences in the physicochemical properties of complex topical ophthalmic suspension formulations is important in drug product development and regulatory assessment. Herein, we used published FDA clinical pharmacology review data, in-house, and literature rabbit pharmacokinetic data generated for dexamethasone ophthalmic suspensions to demonstrate how the mechanistic Ocular Compartmental Absorption and Transit model by GastroPlus™ can be used to characterize ocular drug pharmacokinetic performance in rabbits for suspension formulations. This model was used to describe the dose-dependent (0.01 to 0.1%) non-linear pharmacokinetic in ocular tissues and characterize the impact of viscosity (1.67 to 72.9 cP) and particle size (5.5 to 22 μm) on in vivo ocular drug absorption and disposition. Parameter sensitivity analysis (hypothetical suspension particle size: 1 to 10 μm, viscosity: 1 to 100 cP) demonstrated that the interplay between formulation properties and physiological clearance through drainage and tear turnover rates in the pre-corneal compartment drives the ocular drug bioavailability. The quick removal of drug suspended particles from the pre-corneal compartment renders the impact of particle size inconsequential relative to viscosity modification. The in vivo ocular absorption is (1) viscosity non-sensitive when the viscosity is high and the impact of viscosity on the pre-corneal residence time reaches the maximum physiological system capacity or (2) viscosity sensitive when the viscosity is below a certain limit. This study reinforces our understanding of the interplay between physiological factors and ophthalmic formulation physicochemical properties and their impact on in vivo ocular drug PK performance in rabbits.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Center for Drug Evaluation and Research. Generic drug user fee amendments [Internet]. [cited 2018 Dec 14]. Available from: https://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/default.htm. Accessed 30 Apr 2019.

  2. 2.

    US. FDA. Bioavailability and bioequivalence studies for orally administered drug products—general considerations [Internet]. 2003. Available from: https://www.fda.gov/media/87219/download. Accessed 30 Apr 2019.

  3. 3.

    Choi SH, Lionberger RA. Clinical, pharmacokinetic, and in vitro studies to support bioequivalence of ophthalmic drug products. AAPS J. 2016;18(4):1032–8. https://doi.org/10.1208/s12248-016-9932-z.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Orange book: approved drug products with therapeutic equivalence evaluations [Internet]. [cited 2018 Dec 14]. Available from: https://www.accessdata.fda.gov/scripts/cder/ob/. Accessed 30 Apr 2019.

  5. 5.

    Ali Y, Lehmussaari K. Industrial perspective in ocular drug delivery. Adv Drug Deliv Rev. 2006 Nov 15;58(11):1258–68.

    CAS  Article  Google Scholar 

  6. 6.

    US. FDA. Draft Guidance on Dexamethasone; Tobramycin [Internet]. 2016. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/psg/Dexamethasone Tobramycin_ophthalmic suspension NDA 50818 RV Feb 2019.pdf.. Accessed 30 Apr 2019.

  7. 7.

    US. FDA. Draft guidance on Nepafenac [Internet]. 2016. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/psg/Nepafenac_ophthalmic suspension 0.1_RLD 0021862_RV12-16.pdf. Accessed 30 Apr 2019.

  8. 8.

    US. FDA. Draft guidance on Loteprednol Etabonate [Internet]. 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/psg/Loteprednol Etabonate_draft_Ophthalmic drops susp_RLD 020583_RCO2-18.pdf. Accessed 30 Apr 2019.

  9. 9.

    Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: a systematic Review of published models, applications, and model verification. Drug Metab Dispos. 2015;43(11):1823–37.

    CAS  Article  Google Scholar 

  10. 10.

    Sieg JW, Robinson JR. Mechanistic studies on transcorneal permeation of pilocarpine. J Pharm Sci. 1976;65(12):1816–22.

    CAS  Article  Google Scholar 

  11. 11.

    Himmelstein KJ, Guvenir I, Patton TF. Preliminary pharmacokinetic model of pilocarpine uptake and distribution in the eye. J Pharm Sci. 1978;67(5):603–6.

    CAS  Article  Google Scholar 

  12. 12.

    Hui HW, Robinson JR. Effect of particle dissolution rate on ocular drug bioavailability. J Pharm Sci. 1986;75(3):280–7.

    CAS  Article  Google Scholar 

  13. 13.

    Worakul N, Robinson JR. Ocular pharmacokinetics/pharmacodynamics. Eur J Pharm Biopharm. 1997;44(1):71–83.

    CAS  Article  Google Scholar 

  14. 14.

    Deng F, Ranta V-P, Kidron H, Urtti A. General pharmacokinetic model for topically administered ocular drug dosage forms. Pharm Res. 2016;33(11):2680–90. https://doi.org/10.1007/s11095-016-1993-2.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    del Amo EM, Vellonen K-S, Kidron H, Urtti A. Intravitreal clearance and volume of distribution of compounds in rabbits: in silico prediction and pharmacokinetic simulations for drug development. Eur J Pharm Biopharm. 2015;95(Pt B):215–26.

    PubMed  Google Scholar 

  16. 16.

    Lamminsalo M, Taskinen E, Karvinen T, Subrizi A, Murtomäki L, Urtti A, et al. Extended pharmacokinetic model of the rabbit eye for intravitreal and intracameral injections of macromolecules: quantitative analysis of anterior and posterior elimination pathways. Pharm Res. 2018;35(8):153.

    Article  Google Scholar 

  17. 17.

    Hutton-Smith LA, Gaffney EA, Byrne HM, Maini PK, Gadkar K, Mazer NA. Ocular pharmacokinetics of therapeutic antibodies given by intravitreal injection: estimation of retinal permeabilities using a 3-compartment semi-mechanistic model. Mol Pharm. 2017;14(8):2690–6. https://doi.org/10.1021/acs.molpharmaceut.7b00164.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Rimpelä A-K, Reinisalo M, Hellinen L, Grazhdankin E, Kidron H, Urtti A, et al. Implications of melanin binding in ocular drug delivery. Adv Drug Deliv Rev. 2018;126:23–43.

    Article  Google Scholar 

  19. 19.

    Grass GM, Lee VH. A model to predict aqueous humor and plasma pharmacokinetics of ocularly applied drugs. Invest Ophthalmol Vis Sci. 1993;34(7):2251–9.

    CAS  PubMed  Google Scholar 

  20. 20.

    Walenga RL, Babiskin AH, Zhang X, Absar M, Zhao L, Lionberger RA. Impact of vehicle physicochemical properties on modeling-based predictions of cyclosporine ophthalmic emulsion bioavailability and tear film breakup time. J Pharm Sci. 2019;108(1):620–9.

    CAS  Article  Google Scholar 

  21. 21.

    US. FDA. MAXIDEX®- dexamethasone ophthalmic suspension label [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/013422s045lbl.pdf. Accessed 30 Apr 2019.

  22. 22.

    US. FDA. TOBRADEX® (tobramycin and dexamethasone ophthalmic suspension) label [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/50592slr032_tobradex_lbl.pdf. Accessed 30 Apr 2019.

  23. 23.

    US. FDA. TOBRADEX® ST (tobramycin / dexamethasone ophthalmic suspension) label [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050818lbl.pdf. Accessed 30 Apr 2019.

  24. 24.

    Chockalingam A, Xu L, Stewart S, Le Merdy M, Tsakalozou E, Fan J, et al. Protocol for evaluation of topical ophthalmic drug products in different compartments of fresh eye tissues in a rabbit model. J Pharmacol Toxicol Methods [Internet] 2018. [cited 2018 Dec 17]; Available from: http://www.sciencedirect.com/science/article/pii/S105687191830697X.

  25. 25.

    Matta MK, Narayanasamy S, Thomas CD, Xu L, Stewart S, Chockalingam A, et al. A sensitive UPLC-APCI-MS/MS method for the determination of dexamethasone and its application in an ocular tissue distribution study in rabbits following topical administration. Anal Methods. 2018 May 24;10(20):2307–16.

    CAS  Article  Google Scholar 

  26. 26.

    Dexamethasone [Internet]. [cited 2018 Dec 14]. Available from: https://www.drugbank.ca/drugs/DB01234. Accessed 30 Apr 2019.

  27. 27.

    Obach RS. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos Biol Fate Chem. 1999;27(11):1350–9.

    CAS  PubMed  Google Scholar 

  28. 28.

    Yamashita S, Furubayashi T, Kataoka M, Sakane T, Sezaki H, Tokuda H. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur J Pharm Sci. 2000;10(3):195–204.

    CAS  Article  Google Scholar 

  29. 29.

    Barry BW, El Eini DI. Solubilization of hydrocortisone, dexamethasone, testosterone and progesterone by long-chain polyoxyethylene surfactants. J Pharm Pharmacol. 1976;28(3):210–8.

    CAS  Article  Google Scholar 

  30. 30.

    Choi Stephanie, Wu Yang, Kozak Darby, Zheng J. Physicochemical characterization of Tobradex and Tobradex ST under physiological conditions. Baltimore; 2017.

  31. 31.

    Prausnitz MR, Noonan JS. Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci. 1998;87(12):1479–88.

    CAS  Article  Google Scholar 

  32. 32.

    Hahne M, Zorn-Kruppa M, Guzman G, Brandner JM, Haltner-Ukomado E, Wätzig H, et al. Prevalidation of a human cornea construct as an alternative to animal corneas for in vitro drug absorption studies. J Pharm Sci. 2012;101(8):2976–88. https://doi.org/10.1002/jps.23190.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Patton TF, Robinson JR. Ocular evaluation of polyvinyl alcohol vehicle in rabbits. J Pharm Sci. 1975;64(8):1312–6.

    CAS  Article  Google Scholar 

  34. 34.

    Hosseini K, Matsushima D, Johnson J, Widera G, Nyam K, Kim L, et al. Pharmacokinetic study of dexamethasone disodium phosphate using intravitreal, subconjunctival, and intravenous delivery routes in rabbits. J Ocul Pharmacol Ther. 2008;24(3):301–8.

    CAS  Article  Google Scholar 

  35. 35.

    Schoenwald RD, Stewart P. Effect of particle size on ophthalmic bioavailability of dexamethasone suspensions in rabbits. J Pharm Sci. 1980;69(4):391–4.

    CAS  Article  Google Scholar 

  36. 36.

    Lu AT, Frisella ME, Johnson KC. Dissolution modeling: factors affecting the dissolution rates of polydisperse powders. Pharm Res. 1993;10(9):1308–14.

    CAS  Article  Google Scholar 

  37. 37.

    SimulationPlus. GastroPlus 9.6 manual. 2018. https://doi.org/10.17226/25305.

    Google Scholar 

  38. 38.

    TGA. Australian Public Assessment report for dexamethasone [Internet]. 2016. Available from: https://www.tga.gov.au/sites/default/files/auspar-dexamethasone-161025.docx. Accessed 30 Apr 2019.

  39. 39.

    US. FDA. Pharmacology Review(s) NDA 50-818 [Internet]. 2009. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/050818s000pharmr.pdf. Accessed 30 Apr 2019.

  40. 40.

    Makoid MC, Robinson JR. Pharmacokinetics of topically applied pilocarpine in the albino rabbit eye. J Pharm Sci. 1979;68(4):435–43.

    CAS  Article  Google Scholar 

  41. 41.

    Farkouh A, Frigo P, Czejka M. Systemic side effects of eye drops: a pharmacokinetic perspective. Clin Ophthalmol. 2016;10:2433–41.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jianghong Fan.

Ethics declarations

Disclaimer

This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOCX 85 kb)

ESM 2

(DOCX 23 kb)

ESM 3

(DOCX 17 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Le Merdy, M., Fan, J., Bolger, M.B. et al. Application of Mechanistic Ocular Absorption Modeling and Simulation to Understand the Impact of Formulation Properties on Ophthalmic Bioavailability in Rabbits: a Case Study Using Dexamethasone Suspension. AAPS J 21, 65 (2019). https://doi.org/10.1208/s12248-019-0334-x

Download citation

KEY WORDS

  • bioequivalence
  • dexamethasone
  • ocular PBPK
  • particle size
  • simulation
  • viscosity