Background and ObjectivesThe disposition of azithromycin in the human eye following topical administration has not been fully explored. Population pharmacokinetic (PopPK) modeling can allow useful conclusions to be drawn based on limited tear sampling data. The aim of this study was therefore to develop and evaluate a PopPK model of azithromycin eyedrops in tears, investigate typical model parameters, and identify potential covariates following single-dose ocular instillation.MethodsA total of 84 tear samples were obtained from 42 healthy volunteers at seven time points over 24h following topical administration of azithromycin eyedrops (2.5mL/25mg). Azithromycin concentrations in the tears were determined using a validated LC-MS/MS assay. PopPK analysis was performed using nonlinear mixed-effects modeling. Intraocular pressure, tear secretion measurement, age, and gender were evaluated as possible covariates. Bootstrap and visual predictive checks were used simultaneously to evaluate the PopPK model. The dosage regimen was further estimated based on Monte Carlo simulation and the area under the curve/minimal inhibitory concentration.ResultsA linear two-compartment first-order elimination model was found to best describe the pharmacokinetic profile of azithromycin in tears. None of the covariates had a significant influence on the typical model parameters. The final PopPK model was demonstrated to be suitable and effective according to bootstrap and visual predictive checks. Twice-daily instillation of azithromycin eyedrops would appear to provide the required antibacterial activity.ConclusionA proposed linear two-compartment PopPK model of azithromycin eyedrops was found to be effective at describing the disposition of azithromycin in tears after ocular instillation.