Population Pharmacokinetic Modeling of Azithromycin Eyedrops in Tears Following Single-Dose Topical Administration in Healthy Volunteers

Overview

Journal Eur J Drug Metab Pharmacokinet

Date 2018 Oct 26

PMID 30357610

Authors

Feng Wu

Xiuli Zhao

Xingang Li

Yimin Cui

Affiliations

Soon will be listed here.

Abstract

Background And Objectives: The 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.

Methods: A total of 84 tear samples were obtained from 42 healthy volunteers at seven time points over 24 h following topical administration of azithromycin eyedrops (2.5 mL/25 mg). 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.

Results: A 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.

Conclusion: A 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.

References

Craig W . Does the dose matter?. Clin Infect Dis. 2001; 33 Suppl 3:S233-7. DOI: 10.1086/321854. View

Scuderi A, De Lazzari A, Miano F, Zola P . Residence time of netilmicin in tears. Cornea. 2002; 21(1):48-50. DOI: 10.1097/00003226-200201000-00011. View

Raizman M, Rubin J, Graves A, Rinehart M . Tear concentrations of levofloxacin following topical administration of a single dose of 0.5% levofloxacin ophthalmic solution in healthy volunteers. Clin Ther. 2002; 24(9):1439-50. DOI: 10.1016/s0149-2918(02)80047-9. View

Peric M, Browne F, Jacobs M, Appelbaum P . Activity of nine oral agents against gram-positive and gram-negative bacteria encountered in community-acquired infections: use of pharmacokinetic/pharmacodynamic breakpoints in the comparative assessment of beta-lactam and macrolide antimicrobial.... Clin Ther. 2003; 25(1):169-77. DOI: 10.1016/s0149-2918(03)90021-x. View

Ette E, Williams P, Kim Y, Lane J, Liu M, Capparelli E . Model appropriateness and population pharmacokinetic modeling. J Clin Pharmacol. 2003; 43(6):610-23. View

Jain R, Danziger L . The macrolide antibiotics: a pharmacokinetic and pharmacodynamic overview. Curr Pharm Des. 2004; 10(25):3045-53. DOI: 10.2174/1381612043383322. View

Protzko E, Bowman L, Abelson M, Shapiro A . Phase 3 safety comparisons for 1.0% azithromycin in polymeric mucoadhesive eye drops versus 0.3% tobramycin eye drops for bacterial conjunctivitis. Invest Ophthalmol Vis Sci. 2007; 48(8):3425-9. DOI: 10.1167/iovs.06-1413. View

Chiambaretta F, Garraffo R, Elena P, Pouliquen P, Delval L, Rigal D . Tear concentrations of azithromycin following topical administration of a single dose of azithromycin 0.5%, 1.0%, and 1.5% eyedrops (T1225) in healthy volunteers. Eur J Ophthalmol. 2008; 18(1):13-20. DOI: 10.1177/112067210801800103. View

Abduljalil K, Diestelhorst M, Doroshyenko O, Lux A, Steinfeld A, Dinslage S . Modelling ocular pharmacokinetics of fluorescein administered as lyophilisate or conventional eye drops. Eur J Clin Pharmacol. 2008; 64(5):521-9. DOI: 10.1007/s00228-007-0457-3. View

10.

Miyake K, Ogawa T, Tajika T, Gow J, McNamara T . Ocular pharmacokinetics of a single dose of bromfenac sodium ophthalmic solution 0.1% in human aqueous humor. J Ocul Pharmacol Ther. 2008; 24(6):573-8. DOI: 10.1089/jop.2007.0132. View

11.

Torkildsen G, OBrien T . Conjunctival tissue pharmacokinetic properties of topical azithromycin 1% and moxifloxacin 0.5% ophthalmic solutions: a single-dose, randomized, open-label, active-controlled trial in healthy adult volunteers. Clin Ther. 2008; 30(11):2005-14. DOI: 10.1016/j.clinthera.2008.10.020. View

12.

Bowman L, Si E, Pang J, Archibald R, Friedlaender M . Development of a topical polymeric mucoadhesive ocular delivery system for azithromycin. J Ocul Pharmacol Ther. 2009; 25(2):133-9. DOI: 10.1089/jop.2008.0066. View

13.

Savic R, Karlsson M . Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 2009; 11(3):558-69. PMC: 2758126. DOI: 10.1208/s12248-009-9133-0. View

14.

Friedlaender M, Protzko E . Clinical development of 1% azithromycin in DuraSite, a topical azalide anti-infective for ocular surface therapy. Clin Ophthalmol. 2009; 1(1):3-10. PMC: 2699985. View

15.

Abelson M, Protzko E, Shapiro A, Garces-Soldana A, Bowman L . A randomized trial assessing the clinical efficacy and microbial eradication of 1% azithromycin ophthalmic solution vs tobramycin in adult and pediatric subjects with bacterial conjunctivitis. Clin Ophthalmol. 2009; 1(2):177-82. PMC: 2704516. View

16.

Akpek E, Vittitow J, Verhoeven R, Brubaker K, Amar T, Powell K . Ocular surface distribution and pharmacokinetics of a novel ophthalmic 1% azithromycin formulation. J Ocul Pharmacol Ther. 2009; 25(5):433-9. DOI: 10.1089/jop.2009.0026. View

17.

Walters T, Rinehart M, Krebs W, Holdbrook M . Tear concentration and safety of levofloxacin ophthalmic solution 1.5% compared with ofloxacin ophthalmic solution 0.3% after topical administration in healthy adult volunteers. Cornea. 2010; 29(3):263-8. DOI: 10.1097/ICO.0b013e3181b55fce. View

18.

Stewart W, Crean C, Zink R, Brubaker K, Haque R, Hwang D . Pharmacokinetics of azithromycin and moxifloxacin in human conjunctiva and aqueous humor during and after the approved dosing regimens. Am J Ophthalmol. 2010; 150(5):744-751.e2. DOI: 10.1016/j.ajo.2010.05.039. View

19.

Torkildsen G, Cockrum P, Meier E, Hammonds W, Silverstein B, Silverstein S . Evaluation of clinical efficacy and safety of tobramycin/dexamethasone ophthalmic suspension 0.3%/0.05% compared to azithromycin ophthalmic solution 1% in the treatment of moderate to severe acute blepharitis/blepharoconjunctivitis. Curr Med Res Opin. 2010; 27(1):171-8. DOI: 10.1185/03007995.2010.539603. View

20.

Opitz D, Harthan J . Review of Azithromycin Ophthalmic 1% Solution (AzaSite(®)) for the Treatment of Ocular Infections. Ophthalmol Eye Dis. 2013; 4:1-14. PMC: 3619494. DOI: 10.4137/OED.S7791. View