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Azithromycin eye drops with a bioadhesive ocular drug-delivery system can offer a simplified dosing regimen. In this study, we compared the pharmacokinetic properties and assessed the bioequivalence of a newly developed generic azithromycin eye drop with a branded formulation. This open-label, single-dose, randomized, crossover, sparse-sampling ocular bioequivalence study was conducted on 48 healthy Chinese volunteers. Tear samples were collected for up to 36 hours, and each participant was randomly allocated to one of the prespecified sampling times. Tear drug concentrations were determined using a validated liquid chromatography-tandem mass spectrometry method. The pharmacokinetic parameters were calculated via noncompartmental analysis. A nonparametric bootstrap method was used to obtain 90% confidence intervals (CIs) for the ratios of the test and reference drugs. Tolerability was evaluated for adverse events (AEs). After bootstrapping (1000 iterations), the 90%CIs for the log-transformed ratios of C max , AUC 0-t , and AUC 0-∞ were within the acceptable bioequivalence range (80%-125%). No moderate-to-severe AEs were reported for either formulation. Bioequivalence was demonstrated between the two formulations. The sparse-sampling design with the bootstrapping technique is promising for bioequivalence studies of topical ophthalmic drugs., (© 2023, The American College of Clinical Pharmacology.)

A rapid and sensitive method for the quantitative analysis of azithromycin in human tears by LC-MS/MS was developed and validated. Following extraction from collected Schirmer tear strips by methanol-water (4:1, v/v), the analyte and IS (azithromycin-d3) were separated on a Waters Atlantis™ dC 18 column (2.1 mm × 30 mm, 3 μm) by gradient elution with 0.1% (v/v) formic acid in methanol-water (1:9) and methanol-acetonitrile (9:1) as the mobile phase. Electrospray ionization in positive ion mode and MRM were used to monitor the ion transitions at m/z 749.6 → 591.6 (azithromycin) and 752.4 → 594.4 (azithromycin-d3). The results indicated that the method had excellent sensitivity and specificity. The analyte appeared to have good linearity in the range of 5-1000 ng/ mL. Both the intra-batch and inter-batch precisions (in terms of RSD) were <10%, and the accuracies (in terms of RE) were within ±15%. The lower limit of quantification, matrix effect, extraction recovery, stability and dilution integrity were also evaluated and satisfied the validation criteria. Artificial tears served as the surrogate matrix, and no matrix difference was found when compared with that of real human tears. Finally, this method was successfully applied in an ocular pharmacokinetic study in healthy volunteers following instillation of azithromycin eyedrops.