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J. Proksch, J.-Y. Driot, K. W. Ward; Nonclinical Ocular and Systemic Pharmacokinetics of BOL-303224-A, a Novel Fluoroquinolone Antimicrobial Agent for Topical Ophthalmic Use. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4273.
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Studies were conducted to evaluate the ocular pharmacokinetics (PK) of BOL-303224-A following single and repeated topical ocular administration to pigmented rabbits. These data were used along with in vitro antimicrobial MIC90 values for BOL-303224-A to assess the potential utility of this novel fluoroquinolone to treat ophthalmic infections.
BOL-303224-A or [14C]BOL-303224-A was formulated as a 0.6% aqueous suspension containing polycarbophil, edetate disodium dihydrate, and sodium chloride. Animals received either a single instillation, or repeated (TID for 5 days) instillations. At predetermined intervals after the last dose, blood samples were collected from a marginal ear vein and tear samples were collected from each eye. Following collection of tear samples, animals were euthanized, eyes enucleated, and ocular tissues collected and frozen. Concentrations of BOL-303224-A in plasma and ocular tissues were quantified by LC/MS/MS; the level of carbon-14 in ocular and non-ocular tissues was analyzed by autoradiography or liquid scintillation analysis.
Following a single topical administration of a 0.6% formulation, BOL-303224-A readily penetrated into conjunctiva and aqueous humor, with maximum concentrations of 62791 ng/mL and 1692 ng/mL, respectively. The ocular mean residence time of BOL-303224-A was 7.1, 7.6, and 15.4 hr for tears, conjunctiva, and aqueous humor, respectively. PK modeling from these data indicated that BOL-303224-A is likely to demonstrate efficacy against most ophthalmologic pathogens with a TID dosing regimen. Systemic exposure to BOL-303224-A was low after topical ocular administration, with concentrations in plasma generally <10 ng/mL.
The excellent ocular PK properties of BOL-303224-A along with the broad antimicrobial activity of this compound make it an excellent candidate for the treatment of a variety of ophthalmic infections.
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