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Pharmacokinetics and Efficacy of Bioerodible Dexamethasone Implant in Concanavalin A-induced Uveitic Cataract Rabbit Model

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Abstract

Purpose

To advance therapy for the treatment of concurrent uveitis and post-cataract surgical inflammation; we evaluated pharmacokinetics and pharmacodynamics of Bioerodible Dexamethasone Implant (BDI) containing 0.3 mg of dexamethasone (DXM) in Concanavalin A (Con A) induced uveitis followed by phacoemulsification in New Zealand White (NZW) rabbits.

Methods

The BDI was implanted in the inferior fornix of the capsular bag after intravitreal injection of Con A and ensuing phacoemulsification in NZW rabbits; standard-of-care topical 0.1% dexamethasone drops served as control. DXM was quantified by liquid chromatography-tandem mass spectrometry and pharmacokinetics of DXM in disease vs. healthy eyes was compared. All eyes were assessed clinically using slit lamp biomicroscopy and Draize scoring scale. Retinal thickness and histological analyses were performed to evaluate retinal edema, inflammation and implant biocompatibility respectively.

Results

In Con A-induced inflammatory uveitic cataract model the BDI controlled anterior and posterior segment inflammation as well as retinal thickening more effectively than topical drops. The exposure (AUC0–t) of DXM with BDI is superior in all ocular tissues, while topical drops did not achieve therapeutic posterior segment levels and did not control inflammation nor prevent retinal edema and architectural disruption.

Conclusions

Our results demonstrate the superiority of the BDI in suppressing Con A-induced inflammation and retinal edema in NZW rabbits and highlight the need for sustained bidirectional delivery of potent anti-inflammatory agents for 5 to 6 weeks to optimize clinical outcomes.

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Abbreviations

BDI:

Bioerodible dexamethasone implant

BQL:

Below quantification limit

CME:

Cystoid macular edema

Con A:

Concanavalin A

DXM:

Dexamethasone

EtO:

Ethylene oxide gas

GC-MS:

Gas chromatography mass spectrometry

HPLC:

High performance liquid chromatography

HPMC:

Hydroxypropyl methylcellulose

LC-MS/MS:

Liquid chromatography tandem mass spectrometry

LLOQ:

Lower limit of quantification

MWCO:

Molecular weight cut off

NSAIDs:

Non-steroidal anti-inflammatory drugs

NZW:

New Zealand white rabbits

PCO:

Posterior capsule opacification

PLGA:

Poly(d,l-lactide-co-glycolide)

PVA:

Polyvinyl alcohol

SD-OCT:

Spectral domain optical coherence tomography

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank Bonnie Archer and Christina Mamalis for technical assistance and proof reading. The research was supported by funds from Research to Prevent Blindness and a University of Utah Technology Commercialization Project grant.

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Authors and Affiliations

  1. Department of Ophthalmology, John A Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, Utah, 84132, USA

    Srinivas Rao Chennamaneni, Austin Bohner, Ashlie Bernhisel & Balamurali K. Ambati

  2. iVeena Delivery Systems LLC., John A Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, Utah, 84132, USA

    Srinivas Rao Chennamaneni & Balamurali K. Ambati

Authors
  1. Srinivas Rao Chennamaneni
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  2. Austin Bohner
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Correspondence to Balamurali K. Ambati.

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Chennamaneni, S.R., Bohner, A., Bernhisel, A. et al. Pharmacokinetics and Efficacy of Bioerodible Dexamethasone Implant in Concanavalin A-induced Uveitic Cataract Rabbit Model. Pharm Res 31, 3179–3190 (2014). https://doi.org/10.1007/s11095-014-1410-7

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  • DOI: https://doi.org/10.1007/s11095-014-1410-7

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