June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Validation of Novel Standard Units for Drug Availability Across the Vitreoretinal Interface and Standardization of Interspecies Dose Adjustments
Author Affiliations & Notes
  • Muhammad Abdulrazik
    Innovative Therapeutic Algorithms, East Jerusalem Biomedical Institute, East Jerusalem, Palestine, State of
  • Footnotes
    Commercial Relationships   Muhammad Abdulrazik, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4456. doi:
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      Muhammad Abdulrazik; Validation of Novel Standard Units for Drug Availability Across the Vitreoretinal Interface and Standardization of Interspecies Dose Adjustments. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4456.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Preclinical studies for the development of new intravitreal pharmaceutical interventions are done on eyes of different species with significant variability in vitreous volume, surface area of the vitreoretinal interface, and the mass of the retina. This study aims at validating a standardizing model for enhanced credibility of carrying forward experimental knowledge on intravitreal pharmaceutical technologies from one species to another.

Methods : Following the administration of single 50 µl topical dose of dexamethasone-base 0.1% to the cul-de-sac of one eye of an albino rabbit, dexamethasone was determined in the vitreous cavity and the retina of treated and contralateral eyes at 30, 45, 60, 90, 120, and 360 min. post dosing (n=4 at each time point).
Drug availability standard units for the vitreous (SDU_V) and the retina (SDU_R) were calculated as follows:
SDU_V = [TVD/VV]x[1/RSA]
SDU_R = [RDC]x[TRM]x[1/RSA]
The predicted retinal concentration:
[RDC] = [F]x[TVD]x[RSA/10]x[1/VV]x[1/TRM]
Wherein TVD is the total amount of drug in vitreous cavity (not including drug still bond to an intravitreal drug delivery system/IDDS) following direct intravitreal administration, release from IDDS, or drug administration outside of vitreous cavity. VV is the volume of vitreous cavity (ml), RSA is the surface area of retina (square cm), RDC is the retinal drug concentration (per gr), TRM is the total retinal mass (gr), and F is the predicted impedance to drug penetration at the vitreoretinal interface. Pearson correlation coefficients (PCC) were calculated for pairs of SDU_V and SDU_R at each of the six time points.

Results : Strong positive correlation was evidenced between SDU_V and SDU_R for anterior retina (PCC= 0.9187, p < 0.01) and posterior retina (PCC= 0.9843, p < 0.001) of treated eyes, but not in contralateral eyes. The predicted Intravitreal dexamethasone dose needed to achieve retinal concentration of 100 ng/gr will be 100, 30, 20, and 1 ng for human, macaca mulatta, rabbit, and rat eye respectively.

Conclusions : The proposed model allows for a planned drug availability profile in the vitreous compartment with predictable drug levels in adjacent target tissues, while being able to carry forward the previously gained knowledge from experimentations on different species. The model should be tested in ocular PK's involving molecules other than dexamethasone.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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