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Physiologically Based Pharmacokinetic Model to Support Ophthalmic Suspension Product Development

The AAPS Journal volume 22, Article number: 26 (2020) Cite this article

Abstract

FDA’s Orange Book lists 17 currently marketed active pharmaceutical ingredients (API) formulated within ophthalmic suspensions in which a majority has 90% or more of the API undissolved. We used an ocular physiologically based pharmacokinetic (O-PBPK) model to compare a suspension with a solution for ophthalmic products with dexamethasone (Dex) as the model drug. Simulations with a Dex suspension O-PBPK model previously verified in rabbit were used to characterize the consequences of drug clearance mechanism in the precorneal compartment on pharmacokinetic (PK) exposure and to assess the ocular and systemic PK characteristics of ophthalmic suspensions with different strengths or magnitudes of viscosity. O-PBPK-based simulations show that (1) Dex suspension 0.05% has a 2.5- and 5-fold higher AUC in aqueous humor and plasma, respectively, than the Dex saturated solution; (2) strength increase by 5- and 10-fold induces a respective 2.2- and 3.3-fold increase in aqueous humor and 4.4- and 8.6-fold increase in plasma Cmax and AUC; and (3) increasing formulation viscosity (from 1.6 to 75 cP) causes an overall increase in API available for absorption in the cornea resulting in a higher ocular Cmax and AUC with no significant impact on systemic exposure. This research demonstrates that solid particles present in a suspension can not only help to achieve a higher ocular exposure but also unfavorably raise systemic exposure. A model able to correlate formulation changes to both ocular and plasma exposure is a necessary tool to support ocular product development taking into consideration both local efficacy and systemic safety aspects.

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References

  1. Yellepeddi VK, Palakurthi S. Recent advances in topical ocular drug delivery. J Ocul Pharmacol Ther Off J Assoc Ocul Pharmacol Ther. 2016;32(2):67–82.

    Article  CAS  Google Scholar 

  2. Xu X, Al-Ghabeish M, Rahman Z, Krishnaiah YSR, Yerlikaya F, Yang Y, et al. Formulation and process factors influencing product quality and in vitro performance of ophthalmic ointments. Int J Pharm. 2015;493(1–2):412–25.

    Article  CAS  Google Scholar 

  3. Patel A, Cholkar K, Agrahari V, Mitra AK. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47–64.

    Article  CAS  Google Scholar 

  4. US. FDA. Orange Book: approved drug products with therapeutic equivalence evaluations [Internet]. [cited 2018 Dec 15]. Available from: https://www.accessdata.fda.gov/scripts/cder/ob/ Accessed November 13, 2019

  5. Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 2019 Jan 8;47(D1):D1102–9.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Le Merdy M, Fan J, Bolger MB, Lukacova V, Spires J, Tsakalozou E, 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. 2019 May 20;21(4):65.

    Article  Google Scholar 

  12. US. FDA. MAXIDEX®- dexamethasone ophthalmic suspension Label [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/013422s045lbl.pdf Accessed November 13, 2019

  13. 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 November 13, 2019

  14. US. FDA. TOBRADEX® ST (tobramycin / dexamethasone ophthalmic suspension) Label [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050818lbl.pdf Accessed November 13, 2019

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Stephanie C, Wu Y, Darby K, Zheng J, Petrochenko P. Physicochemical characterization of Tobradex and Tobradex ST under physiological conditions. Invest Ophthalmol Vis Sci. 2017 8:4459.

    Google Scholar 

  18. 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. 2019 1;96:9-14.

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

    Article  CAS  Google Scholar 

  20. Sasaki H, Yamamura K, Mukai T, Nishida K, Nakamura J, Nakashima M, et al. Pharmacokinetic prediction of the ocular absorption of an instilled drug with ophthalmic viscous vehicle. Biol Pharm Bull. 2000;23(11):1352–6.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

    Maxime Le Merdy, Ming-Liang Tan, Andrew Babiskin & Liang Zhao

Authors
  1. Maxime Le Merdy
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  2. Ming-Liang Tan
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  3. Andrew Babiskin
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  4. Liang Zhao
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Correspondence to Andrew Babiskin.

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Le Merdy, M., Tan, ML., Babiskin, A. et al. Physiologically Based Pharmacokinetic Model to Support Ophthalmic Suspension Product Development. AAPS J 22, 26 (2020). https://doi.org/10.1208/s12248-019-0408-9

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KEY WORDS

  • ocular PBPK
  • ophthalmic suspension
  • PBPK
  • product development