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R. Peterson, O. Mansuri; Pharmacokinetics and Pharmacodynamics of the Anterior Segment . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3587.
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Develop a computer program that models anterior chamber aqueous fluid dynamics and use this program to analyze the pharmacokinetics and pharmacodynamics of antibiotics in the anterior segment.
A simple program was developed starting with a linear ordinary differential equation describing a simplified anterior chamber with perfect mixing, constant volume, and an inflow of aqueous with zero concentration
of antibiotic. The equation is dC/dt = –rC/V where V= volume of anterior chamber, r = aqueous flow rate, and C =
concentration as a function of time. The solution C(t) = Co exp(–rt/V) , where Co is the initial concentration of
antibiotic in the aqueous, results. A broader equation was used to allow for the addition of antibiotic to the system
as time progresses. Area under the curve calculations were performed by definite integer resulting in
classic AUC(area under the concentration time curve), and AUC/MIC(ratio of the AUC to the minimum inhibitory concentration) estimates. The program also yields estimates of Cmax, Cmax/MIC, and Time C exceeds the MIC. These values are useful in evaluating the likely effectiveness of time dependant and concentration dependant antibiotics against various bacteria.
Aqueous humor concentrations of Moxifloxacin ranging from 2.28ug/ml to .88ug/ml were chosen as Cmax ranges based on multiple human studies. Gatifloxacin aqueous humor concentrations ranging from 1.26ug/ml to .48ug/ml were chosen as Cmax ranges. A range of dosing intervals from every 10min to every 6hrs was examined. Various gram positive and gram negative bacteria with differing MIC50’s to Moxifloxacin and Gatifloxacin were used to develop Cmax/MIC and AUC/MIC values for multiple time intervals.
For gram positive species with MIC50’s ranging from .03 ug/ml to .13ug/ml topical administration of Moxifloxacin produced AUC/MIC (12 hr) exceeding 150 for all dosing intervals. Cmax/MIC values ranged from a minimum of 7 to a maximum of 51 depending on the dosing interval and the MIC50 of the bacterial species. Gatifloxacin AUC/MIC and Cmax/MIC values were lower but therapeutic under the majority of dosing intervals.
A program modeling anterior chamber aqueous fluid dynamics was developed which can be used to generate pharmacokinetic an pharmacodynamic parameters useful for predicting the success of antibiotic for treating and preventing anterior segment infection.
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