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Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a Proof-of-Concept Pharmacokinetic Study

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Abstract

Purpose

To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection.

Methods

Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used.

Results

Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points.

Conclusion

The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.

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Abbreviations

ANM:

Anterior nasal mucosa

AUC:

Area under drug concentration-time curve

AUCall :

Area under drug concentration-time curve from time zero to the last time point in the study

AUCextrap :

Extrapolated area under drug concentration-time curve

AUC0-t :

Area under drug concentration-time curve from time zero to the time of last measurable concentration

AUCt-inf :

Area under drug concentration-time curve from time zero to infinity

C0 :

Initial concentration

Clast :

Last observed concentration

Cmax :

Maximum concentration

CRS:

Chronic rhinosinusitis

CV:

Coefficient of variation

DGAV:

Direção Geral de Alimentação e Veterinária, HPLC, high-performance liquid chromatography

IN:

Intranasal

IS:

Internal standard

IV:

Intravenous

k e :

Apparent elimination rate constant

LEV:

Levofloxacin

LLOQ:

Lower limit of quantification

MCC:

Mucociliary clearance

MRT:

Mean residence time

ND:

Not determined

PF-127:

Pluronic F-127

PNM:

Posterior nasal mucosa

QC:

Quality control sample

QCDil :

Quality control after sample dilution

QCH :

Quality control at high concentration

QCL :

Quality control at low concentration

QCLLOQ :

Quality control at the lower limit of quantification

QCM :

Quality control at medium concentration

TEA:

Triethylamine

t1/2 :

Elimination half-life

tmax :

Time to attain maximum concentration

References

  1. Anderson VR, Perry CM. Levofloxacin: a review of its use as a high-dose, short-course treatment for bacterial infection. Drugs. 2008;68(4):535–65.

    Article  CAS  PubMed  Google Scholar 

  2. Ball P. Efficacy and safety of levofloxacin in the context of other contemporary fluoroquinolones: a review. Curr Ther Res Clin Exp. 2003;64(9):646–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Davis R, Bryson HM. Levofloxacin. A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs. 1994;47(4):677–700.

    Article  CAS  PubMed  Google Scholar 

  4. Sousa J, Alves G, Fortuna A, Falcão A. Third and fourth generation fluoroquinolone antibacterials: a systematic review of safety and toxicity profiles. Curr Drug Saf. 2014;9(2):89–105.

    Article  CAS  PubMed  Google Scholar 

  5. Zhanel GG, Ennis K, Vercaigne L, Walkty A, Gin AS, Embil J, et al. A critical review of the fluoroquinolones: focus on respiratory infections. Drugs. 2002;62(1):13–59.

    Article  CAS  PubMed  Google Scholar 

  6. Cain RB, Lal D. Update on the management of chronic rhinosinusitis. Infect Drug Resist. 2013;6:1–14.

    PubMed  PubMed Central  Google Scholar 

  7. Elliott KA, Stringer SP. Evidence-based recommendations for antimicrobial nasal washes in chronic rhinosinusitis. Am J Rhinol. 2006;20(1):1–6.

    PubMed  Google Scholar 

  8. Ezzat WF, Fawaz SA, Rabie H, Hamdy TA, Shokry YA. Effect of topical ofloxacin on bacterial biofilms in refractory post-sinus surgery rhino-sinusitis. Eur Arch Otorhinolaryngol. 2015;272(9):2355–61.

    Article  CAS  PubMed  Google Scholar 

  9. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N, Cervin A, Douglas R, Gevaert P, Georgalas C, Goossens H, Harvey R, Hellings P, Hopkins C, Jones N, Joos G, Kalogjera L, Kern B, Kowalski M, Price D, Riechelmann H, Schlosser R, Senior B, Thomas M, Toskala E, Voegels R, de Wang Y, Wormald PJ. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 2012;50(1):1–12.

  10. Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Kumar KA, Kramper M, et al. Clinical practice guideline (update): Adult Sinusitis Executive Summary. Otolaryngol Head Neck Surg. 2015;152(4):598–609.

    Article  PubMed  Google Scholar 

  11. SchwartzJS TBA, Cohen NA. Medical Management of Chronic Rhinosinusitis – an update. Expert Rev Clin Pharmacol. 2016;9(5):695–704.

    Article  Google Scholar 

  12. Bendouah Z, Barbeau J, Hamad WA, Desrosiers M. Biofilm formation by Staphylococcus Aureus and Pseudomonas Aeruginosa is associated with an unfavorable evolution after surgery for chronic sinusitis and nasal polyposis. Otolaryngol Head Neck Surg. 2006;134(6):991–6.

    Article  PubMed  Google Scholar 

  13. Cohen M, Kofonow J, Nayak JV, Palmer JN, Chiu AG, Leid JG, et al. Biofilms in chronic rhinosinusitis: a review. Am J Rhinol Allergy. 2009;23(3):255–60.

    Article  PubMed  Google Scholar 

  14. Suh JD, Kennedy DW. Treatment options for chronic Rhinosinusitis. Proc Am Thorac Soc. 2011;8:132–40.

    Article  CAS  PubMed  Google Scholar 

  15. Lim M, Citardi MJ, Leong JL. Topical antimicrobials in the management of chronic rhinosinusitis: a systematic review. Am J Rhinol. 2008;22:381–9.

    Article  PubMed  Google Scholar 

  16. Wei W, Yang H, Hu L, Ye Y, Li J. Activity of levofloxacin in combination with colistin against Acinetobacter baumannii: In vitro and in a Galleria mellonella model. J Microbiol Immunol Infect. 2015; doi:10.1016/j.jmii.2015.10.010.

  17. Scheinberg PA, Otsuji A. Nebulized antibiotics for the treatment of acute exacerbations of chronic rhinosinusitis. Ear Nose Throat J. 2002;81(9):648–52.

    PubMed  Google Scholar 

  18. Vaughan WC, Carvalho G. Use of nebulized antibiotics for acute infections in chronic sinusitis. Ann Pharmacother. 2002;127(6):558–68.

    Google Scholar 

  19. Desrosiers MY, Kilty SJ. Treatment alternatives for chronic rhinosinusitis persisting after ESS: what to do when antibiotics, steroids and surgery fail. Rhinology. 2008;46(1):3–14.

    PubMed  Google Scholar 

  20. Prince AA, Steiger JD, Khalid AN, Dogrhamji L, Reger C, Eau Claire S, et al. Prevalence of biofilm-forming bacteria in chronic rhinosinusitis. Am J Rhinol. 2008;2(3):239–45.

    Article  Google Scholar 

  21. Anderson MI, MacGowan AP. Development of the quinolones. J Antimicrob Chemother. 2003;51(1):1–11.

    Article  Google Scholar 

  22. European Directive 2010/63/EU of the European Parliament and of the Council of 22. On the protection of animals used for scientific purposes. Off J Eur Union. September 2010;276:33–79.

    Google Scholar 

  23. Schmolka IR. Artificial skin I. Preparation and properties of pluronic F-127gels for treatment of burns. J Biomed Mater Res. 1972;6:571–82.

    Article  CAS  PubMed  Google Scholar 

  24. Sousa J, Alves G, Fortuna A, Pena A, Lino C, Falcão A. Development and validation of a fast isocratic liquid chromatography method for the simultaneous determination of norfloxacin, lomefloxacin and ciprofloxacin in human plasma. Biomed Chromatogr. 2010;25:535–41.

  25. Gehanno P, Darantière S, Dubreuil C, Chobaut JC, Bobin S, Pages JC, et al. A prospective, multicentre study of moxifloxacin concentrations in the sinus mucosa tissue of patients undergoing elective surgery of the sinus. J Antimicrob Chemother. 2002;49(5):821–6.

    Article  CAS  PubMed  Google Scholar 

  26. Pea F, Marioni G, Pavan F, Staffieri C, Bottin R, Staffieri A, et al. Penetration of levofloxacin into paranasal sinuses mucosa of patients with chronic rhinosinusitis after a single 500 mg oral dose. Pharmacol Res. 2007;55(1):38–41.

    Article  CAS  PubMed  Google Scholar 

  27. European Medicines Agency. Guideline on Bioanalytical Method Validation. 2011. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf.

  28. U.S. Food and Drug Administration. Guidance for Industry: Bioanalytical Method Validation. 2001. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf.

  29. Harkema JR, Carey SA, Wagner JG. The nose revisited: a brief review of the comparative structure, function, and toxicologic pathology of the nasal epithelium. Toxicol Pathol. 2006;34:252–69.

    Article  CAS  PubMed  Google Scholar 

  30. Craig J, Goyal P. Topical and intravenous antibiotics. In: Batra PS, Han JK, editors. Practical medical and surgical Management of Chronic Rhinosinusitis. Switzerland: Springer International Publishing; 2015. p. 253–65.

    Chapter  Google Scholar 

  31. Fujieda Y, Yamaoka K, Ito T, Nakagawa T. Local absorption kinetics of levofloxacin from intestinal tract into portal vein in conscious rat using portal-venous concentration difference. Pharm Res. 1996;13(8):1201–4.

    Article  CAS  PubMed  Google Scholar 

  32. Abdelkader H, Mansour HF. Comparative studies for ciprofloxacin hydrochloride pre-formed gels and thermally triggered (in situ) gels: in vitro and in vivo appraisal using a bacterial keratitis model in rabbits. Pharm Dev Technol. 2015;20(4):410–6.

    Article  CAS  PubMed  Google Scholar 

  33. Bankhele SC, Harale RB, Rao MRP, Dhoka MV. Thermoreversible in-situ ophthalmic gelling system of LevofloxacinHemihydrate: formulation and optimization by factorial design. Asian J Pharm Res. 2012;2(3):100–6.

    Google Scholar 

  34. Bhandwalkar MJ, Avachat AM. Thermoreversible nasal in situ gel of venlafaxine hydrochloride: formulation, characterization, and pharmacodynamic evaluation. AAPS PharmSciTech. 2013;14(1):101–10.

    Article  CAS  PubMed  Google Scholar 

  35. Jagdale S, Shewale N, Kuchekar BS. Optimization of ThermoreversibleIn situ nasal gel of Timolol maleate. Scientifica. 2016;2016:1–11.

    Article  Google Scholar 

  36. Majithiya RJ, Ghosh PK, Umrethia ML, Murthy RS. Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan. AAPS PharmSciTech. 2006;7(3):E1–7.

    Article  Google Scholar 

  37. Pathak R, Prasad DR, Misra M, Nivsarkar M. Role of mucoadhesive polymers in enhancing delivery of nimodipinemicroemulsion to brain via intranasal route. Acta Pharm Sin B. 2014;4(2):151–60.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Perez AP, Mundiña-Weilenmann C, Romero EL, Morilla MJ. Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels. Int J Nanomedicine. 2012;7:1373–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Rao M, Agrawal DK, Shirsath C. Thermoreversible mucoadhesive in situ nasal gel for treatment of Parkinson's disease. Drug Dev Ind Pharm. 2016;1:1–9.

    Google Scholar 

  40. Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokinet. 1997;32(2):101–19.

    Article  CAS  PubMed  Google Scholar 

  41. Sharma PC, Jain A, Jain S. Fluoroquinolone antibacterials: a review on chemistry, microbiology and therapeutic prospects. Acta Pol Pharm. 2009;66(6):587–604.

    CAS  PubMed  Google Scholar 

  42. Morgan KT, Jiang XZ, Patterson DL, Gross EA. The nasal mucociliary apparatus. Correlation of structure and function in the rat. Am Rev Respir Dis. 1984;130(2):275–81.

    CAS  PubMed  Google Scholar 

  43. Aliabadi HM, Shahin M, Brocks DR, Lavasanifar A. Disposition of drugs in block copolymer micelle delivery systems from discovery to recovery. Clin Pharmacokinet. 2008;47(10):619–34.

    Article  CAS  PubMed  Google Scholar 

  44. Anand U, Feridooni T, Agu RU. Novel mucoadhesive polymers for nasal drug delivery. In: Sezer AD, ed. Recent Advances in Novel Drug Carrier Systems, INTECH Open Access Publisher; 2012:315–330.

  45. Anderson BC, Pandit NK, Mallapragada SK. Understanding drug release from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) gels. J Control Release. 2001;70(1–2):157–67.

    Article  CAS  PubMed  Google Scholar 

  46. Taha EI, Badran MM, El-Anazi MH, Bayomi MA, El-Bagory IM. Role of Pluronic F127 micelles in enhancing ocular delivery of ciprofloxacin. J Mol Liq. 2014;199:251–6.

    Article  CAS  Google Scholar 

  47. Yang L, Alexandridis P. Physicochemical aspects of drug delivery and release from polymer-based colloids. Curr Opin Colloid Interface Sci. 2000;5:132–43.

    Article  CAS  Google Scholar 

  48. Gonda I, Gipps E. Model of disposition of drugs administered into the human nasal cavity. Pharm Res. 1990;7(1):69–75.

    Article  CAS  PubMed  Google Scholar 

  49. Swamy NGN, Abbas Z. Mucoadhesive in situ gels as nasal drug delivery systems: an overview. Asian J Pharm Sci. 2012;7:168–80.

    Google Scholar 

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Acknowledgments and Disclosures

This work was supported by Fundação para a Ciência e a Tecnologia (FCT, Portugal) through the grant SFRH/BD/69378/2010 within POPH (Programa Operacional Potencial Humano) which is co-funded by FSE (Fundo Social Europeu, União Europeia). The authors have declared no conflict of interest.

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Authors and Affiliations

  1. Pharmacology Department, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal

    Joana Sousa, Ana Fortuna & Amílcar Falcão

  2. CNC – Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal

    Joana Sousa, Gilberto Alves, Ana Fortuna & Amílcar Falcão

  3. CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal

    Gilberto Alves

  4. Faculty of Health Sciences, CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal

    Gilberto Alves

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  1. Joana Sousa
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  2. Gilberto Alves
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  4. Amílcar Falcão
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Correspondence to Gilberto Alves.

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Sousa, J., Alves, G., Fortuna, A. et al. Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a Proof-of-Concept Pharmacokinetic Study. Pharm Res 34, 2260–2269 (2017). https://doi.org/10.1007/s11095-017-2232-1

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