Phase I Study in Healthy Women of a Novel Antimycotic Vaginal Ovule Combining Econazole and Benzydamine

A F D Di Stefano, M M Radicioni, A Vaccani, G Caccia, F Focanti, E Salvatori, F Pelacchi, R Picollo, M T Rosignoli, S Olivieri, G Bovi, A Comandini, A F D Di Stefano, M M Radicioni, A Vaccani, G Caccia, F Focanti, E Salvatori, F Pelacchi, R Picollo, M T Rosignoli, S Olivieri, G Bovi, A Comandini

Abstract

Purpose: A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulated in vaginal ovules was investigated in a randomised, double-blind, four-parallel group, tolerability, and pharmacokinetic Phase I study in healthy women.

Methods: The fixed-dose combination was compared to econazole and benzydamine single-drug formulations and with placebo after daily applications for 3 consecutive days. Safety and tolerability were evaluated recording the adverse drug reactions, local and general tolerability scores, clinical laboratory assays, and vital signs. Econazole, benzydamine, and its metabolite benzydamine N-oxide pharmacokinetics were investigated after single and multiple applications.

Results: Local reactions were generally absent. Pruritus and pain at the application site were infrequently reported. According to the subjects' evaluations, the overall tolerability of the ovules was rated as excellent or good. No significant effect of any treatment on laboratory parameters, vital signs, body weight, vaginal pH, or ECG was observed. Very low econazole, benzydamine, and benzydamine-N-oxide concentrations were measured in plasma, though quantifiable in almost all samples.

Conclusion: The tested fixed-dose combination showed a good safety profile consistently with the known tolerability of both active substances. In addition, the confirmed low bioavailability of the drugs excludes the possibility of any accumulation effects and limits the risk of undesired systemic effects. This trial is registered at ClinicalTrials.gov with the identifier NCT02720783 last updated on 07 February 2017.

Conflict of interest statement

All the authors had conflicting interests: Angelini S.p.A., Italy, gave the financial support to the project. The relationships between the Sponsor, Angelini S.p.A., and CROSS Research S.A. and Ospedale Regionale di Mendrisio, Switzerland, were regulated by financial agreements. The Sponsor (FF, ES, FP, RP, MTR, SO, GB and AC) reviewed and approved the study design, was informed about the collection of data, reviewed and approved the analysis and the interpretation of data, and reviewed and approved the manuscript for publication.

Copyright © 2020 A. F. D. Di Stefano et al.

Figures

Figure 1
Figure 1
Mean (±SD) econazole concentration (ng/mL) vs. time profiles on Day 1 of treatment with T (N = 10) and R1 (N = 6) (top) and on Day 3 of treatment with T (N = 12) and R1 (N = 12) (bottom). Linear scale.
Figure 2
Figure 2
Mean (±SD) econazole concentration (ng/mL) vs. time profiles on Days 1 (N = 10) and 3 (N = 12) of treatment with T. Linear scale.
Figure 3
Figure 3
Mean (±SD) benzydamine concentration (ng/mL) vs. time profiles on Day 1 (top) and on Day 3 of treatment with T (N = 13) and R2 (N = 12) (bottom). Linear scale.
Figure 4
Figure 4
Mean (±SD) benzydamine concentration (ng/mL) vs. time profiles on Days 1 and 3 of treatment with T (N = 13). Linear scale.

References

    1. Richter S. S., Galask R. P., Messer S. A., Hollis R. J., Diekema D. J., Pfaller M. A. Antifungal susceptibilities of Candida species causing vulvovaginitis and epidemiology of recurrent cases. Journal of Clinical Microbiology. 2005;43(5):2155–2162. doi: 10.1128/JCM.43.5.2155-2162.2005.
    1. Nyirjesy P., Seeney S. M., Grody M. H., Jordan C. A., Buckley H. R. Chronic fungal vaginitis: the value of cultures. American Journal of Obstetrics and Gynecology. 1995;173, 3, Part 1:820–823. doi: 10.1016/0002-9378(95)90347-x.
    1. Sobel J. D., Chaim W. Treatment of Torulopsis glabrata vaginitis: retrospective review of boric acid therapy. Clinical Infectious Diseases. 1997;24(4):649–652. doi: 10.1093/clind/24.4.649.
    1. Spinillo A., Capuzzo E., Gulminetti R., Marone P., Colonna L., Piazzi G. Prevalence of and risk factors for fungal vaginitis caused by non-albicans species. American Journal of Obstetrics and Gynecology. 1997;176, 1, Part 1:138–141. doi: 10.1016/s0002-9378(97)80026-9.
    1. Corsello S., Spinillo A., Osnengo G., et al. An epidemiological survey of vulvovaginal candidiasis in Italy. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2003;110(1):66–72. doi: 10.1016/S0301-2115(03)00096-4.
    1. Holland J., Young M. L., Lee O., Chen S. C. A. Vulvovaginal carriage of yeasts other than Candida albicans. Sexually Transmitted Infections. 2003;79(3):249–250. doi: 10.1136/sti.79.3.249.
    1. Vermitsky J. P., Self M. J., Chadwick S. G., et al. Survey of vaginal-flora Candida species isolates from women of different age groups by use of species-specific PCR detection. Journal of Clinical Microbiology. 2008;46(4):1501–1503. doi: 10.1128/JCM.02485-07.
    1. Hilton A. L., Warnock D. W. Vaginal candidiasis and the role of the digestive tract as a source of infection. British Journal of Obstetrics and Gynaecology. 1975;82(11):922–926. doi: 10.1111/j.1471-0528.1975.tb00599.x.
    1. Oriel J. D., Partridge B. M., Denny M. J., Coleman J. C. Genital yeast Infections. BMJ. 1972;4(5843):761–764. doi: 10.1136/bmj.4.5843.761.
    1. Willmott F. E. Genital yeasts in female patients attending a VD clinic. The British Journal of Venereal Diseases. 1975;51(2):119–122. doi: 10.1136/sti.51.2.119.
    1. Sobel J. D., Faro S., Force R. W., et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. American Journal of Obstetrics and Gynecology. 1998;178(2):203–211. doi: 10.1016/s0002-9378(98)80001-x.
    1. Mårdh P. A., Rodrigues A. G., Genç M., Novikova N., Martinez-de-Oliveira J., Guaschino S. Facts and myths on recurrent vulvovaginal candidosis--a review on epidemiology, clinical manifestations, diagnosis, pathogenesis and therapy. International Journal of STD & AIDS. 2002;13(8):522–539. doi: 10.1258/095646202760159639.
    1. Aballéa S., Guelfucci F., Wagner J., et al. Subjective health status and health-related quality of life among women with Recurrent Vulvovaginal Candidosis (RVVC) in Europe and the USA. Health and Quality of Life Outcomes. 2013;11(1):p. 169. doi: 10.1186/1477-7525-11-169.
    1. Heel R. C., Brogden R. N., Speight T. M., Avery G. S. Econazole: a review of its antifungal activity and therapeutic efficacy. Drugs. 1978;16(3):177–201. doi: 10.2165/00003495-197816030-00001.
    1. Bergan T., Vangdal M. In vitro activity of antifungal agents against yeast species. Chemotherapy. 1983;29(2):104–110. doi: 10.1159/000238182.
    1. Odds F. C., Abbott A. B., Pye G., Troke P. F. Improved method for estimation of azole antifungal inhibitory concentrations against Candida species, based on azole/antibiotic interactions. Journal of Medical and Veterinary Mycology. 1986;24(4):305–311. doi: 10.1080/02681218680000461.
    1. Schar G., Kayser F. H., Dupont M. C. Antimicrobial activity of econazole and miconazole in vitro and in experimental candidiasis and aspergillosis. Chemotherapy. 1976;22(3-4):211–220. doi: 10.1159/000221928.
    1. Thienpont D., Van Cutsem J., Van Nueten J. M., Niemegeers C. J. E., Marsboom R. Bilogical and toxicological properties of econazole, a broad-spectrum antimycotic. Arzneimittel Forschung. 1975;25(2):224–230.
    1. Georgopapadakou N. H., Walsh T. J. Antifungal agents: chemotherapeutic targets and immunologic strategies. Antimicrobial Agents and Chemotherapy. 1996;40(2):279–291.
    1. Ghannoum M. A. Future of antimycotic therapy. Dermatologic Therapy. 1997;3:104–111.
    1. Koltin Y., Hitchcock C. A. The search for new triazole antifungal agents. Current Opinion in Chemical Biology. 1997;1(2):176–182. doi: 10.1016/s1367-5931(97)80007-5.
    1. White T. C., Marr K. A., Bowden R. A. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clinical Microbiology Reviews. 1998;11(2):382–402.
    1. Fromtling R. A. Overview of medically important antifungal azole derivatives. Clinical Microbiology Reviews. 1988;1(2):187–217. doi: 10.1128/cmr.1.2.187.
    1. Gyno-Pevaryl®. Information professionnelle du Compendium Suisse des Médicaments®. Switzerland: 2014.
    1. de Cecco L., Capitanio G. L., Gerbaldo D., Mannari M., Rissone R. Benzydamine topical treatment of a specific cervicovaginitis with eversion of columnar epithelium. Advances in Gynecological Endocrinology. 1988;2:p. 299.
    1. Martella E., Balbi C., Balbi G. C. Terapia topica delle flogosi vaginali in gravidanza. In: Fioretti P., Silvestrini B., Esposito G., editors. La terapia topica in ginecologia. Milan: Società milanese di studi ginecologici; 1987. pp. 33–38.
    1. Frateschi M., Vigano R., Ossi C. Vaginiti aspecifiche recidivanti: proposta terapeutica. Giornale Italiano di ostetricia e ginecologia. 1990;12(8):571–574.
    1. Pullè C., Sturlese E. Clinical trial comparing the activity and efficacy of ibuprofen isobutanolammonium vs benzydamine hydrochloride, applied as vaginal irrigations, in patients with vaginitis. Clinical and Experimental Obstetrics & Gynecology. 2002;29(3):173–179.
    1. Catanese B., Facchini V., Barillari G., Putzolu S. Serum levels of benzydamine following the topical use of this drug in gynecology. Clinical and Experimental Obstetrics & Gynecology. 1980;7(2):84–88.
    1. Baldock G. A., Brodie R. R., Chasseaud L. F., Taylor T., Walmsley L. M. Pharmacokinetics of benzydamine after intravenous, oral and topical doses to human subjects. Biopharmaceutics & Drug Disposition. 1991;12(7):481–492. doi: 10.1002/bdd.2510120702.
    1. Catanese B., Laganà A., Marino A., Picollo R., Rotatori M. HPLC determination of benzydamine and its metabolite N-oxide in plasma following oral administration or topical application in man, using fluorimetric detection. Pharmacological Research Communications. 1986;18(4):385–403. doi: 10.1016/0031-6989(86)90091-3.
    1. Maamer M., Aurousseau M., Colau J. C. Concentration of benzydamine in vaginal mucosa following local application: an experimental and clinical study. International Journal of Tissue Reactions. 1987;9(2):135–145.
    1. Mahon W. A., De Gregorio M. Benzydamine: a critical review of clinical data. International Journal of Tissue Reactions. 1985;7(3):229–235.
    1. Ginetantum® 0.1% vaginal solution, summary of product characteristics. Italy: 2015.
    1. ICH harmonised tripartite guideline. Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals M3(R1) ICH; 2013. recommended for adoption at step 4 of the ICH process on 16 July 1997 and amended on 9 November 2000 by the ICH steering committee.
    1. US Department of Health and Human Services and US Department of Agriculture. Nutrition and your health: dietary guidelines for Americans. USDA; 2005.
    1. Rindt W., Geibel W. Blut- und Gewebsspiegel des Antimykotikums Econazol nach vaginaler Applikation. Archiv für Gynäkologie. 1977;224(1-4):p. 458. doi: 10.1007/bf00679658.
    1. Rindt W., Geibel W., Appel L. Vaginal absorption of econazole. Arzneimittel Forschung. 1979;29(4):697–699.
    1. Vukovich A., Heald M. A., Darragh A. Vaginal absorption of two imidazole antifungal agents, econazole and miconazole. Clinical Pharmacology and Therapeutics. 1977;21:p. 121.
    1. Bonelli A., Rosignoli M. T., Esposito G., et al. Phase III study to evaluate the efficacy of a novel antimycotic vaginal pessary combination (containing benzydamine HCl 6 mg and econazole nitrate 150 mg) in the treatment of uncomplicated vulvovaginal candidosis (VVC). 13th Congress of the European Society of Gynecology, Vienna; 2019; Vienna.

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