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J. L. Vittitow, A. J. Parham, W. M. Bodnar, C. S. Crean; Pharmacokinetic Modeling of Azithromycin in Rabbit Eyelids Following Topical Ocular Administration of AzaSite®. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2672.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate and mathematically model the pharmacokinetics (PK) of a proprietary, polycarbophil-containing formulation of azithromycin (AZM) in rabbit eyelids following topical administration.
Dutch-belted rabbits were instilled with 30 µL of AZM ophthalmic solution 1% to the right cornea. Drug was administered BID (0800 and 1700) on days 1 and 2 and QD (0800) on days 3-7. Eyelids were collected preinstillation, 0.5 and 1 h following the 0800 instillation on days 1-6 and at multiple time points for 16 days after the last instillation on day 7 (144 h after 1st administration). AZM levels were measured by LC/MS/MS and PK analysis was conducted with Winnonlin v5.2. A mathematical PK model was developed based on the above data and validated with a second study involving a different administration paradigm, where drug was instilled QD (0800) on days 1-7 and 15-21 and eyelids collected Qam (0800) on days 15, 22 and 30.
In the first dosing paradigm, peak eyelid concentrations increased over the course of administration with Cmax of 180.3 µg/g on Day 7. The AUC0-144h prior to the last administration was 8,926 µg*h/g, whereas the total observed AUC0-504h was 21,813 µg*h/g. AZM exhibited a terminal elimination half-life of 193 h. A 3-compartment model with 15 minute constant order drug input after each instillation was developed that demonstrated a 94.3% correlation between predicted and observed concentrations from the model development study. Predicted eyelid concentrations from the validation study were within the 90% confidence interval (CI) of the experimental data on Days 15 [28.4 µg/g, CI (28.4-40.6)], 22 [88.8 µg/g, CI (49.2-91.1)] and 30 [23.8 µg/g, CI (21.0-39.1)].
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