Advances in Therapy

, Volume 33, Issue 12, pp 2229–2241 | Cite as

Lack of a Pharmacokinetic Interaction Between SYM-1219 Granules Containing 2 Grams of Secnidazole and a Combined Oral Contraceptive in a Phase 1, Randomized, Open-Label Study in Healthy Female Volunteers

  • Helen S. Pentikis
  • Nikki Adetoro
  • Carol J. Braun
Original Research

Abstract

Introduction

Bacterial vaginosis (BV) is a serious infection that is the most common vaginal infection in women of childbearing potential. SYM-1219 is a novel, granule formulation containing 2 g of secnidazole that is being developed as a single, oral dose to treat women with BV. Because many of the women diagnosed with BV use hormonal contraception, the effect of SYM-1219 on the pharmacokinetics (PK) of commonly prescribed oral contraceptive drugs, ethinyl estradiol (EE2), and norethindrone (NET) was evaluated.

Methods

This two-period, randomized, open-label study examined effects in 54 healthy female subjects. During the first period of the study, each subject received EE2 0.035-mg/NET 1-mg tablets. During the second period of the study, subjects were randomized to receive either EE2 0.035-mg/NET 1-mg tablets with concomitant 2-g SYM-1219 or 2-g SYM-1219 followed by EE2 0.035-mg/NET 1-mg tablets 1 day later. The PK of EE2 and NET were analyzed for 24 h following administration.

Results

Coadministration of SYM-1219 and EE2/NET, either on the same day or 1 day apart, had no clinically relevant effects on the bioavailability of EE2 or NET. The combined use of SYM-1219 with EE2/NET was well tolerated. Taken together, these results indicate that contraceptive efficacy should be maintained during coadministration of SYM-1219 and EE2/NET.

Conclusion

SYM-1219 is a valuable single-dose treatment option for women with BV that will not interfere with combined oral contraceptive methods.

Funding

Symbiomix Therapeutics.

Keywords

Bacterial vaginosis Clinical trial Infectious diseases Oral contraceptives Pharmacokinetics Secnidazole 

Notes

Acknowledgments

Sponsorship and article processing charges for this study were funded by Symbiomix Therapeutics. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. The authors would like to thank Chantelle Rein-Smith, Ph.D., of Whitsell Innovations, Inc. for aid in manuscript preparation (funded by Symbiomix Therapeutics) and Sara Obregon for timeline, contract, and vendor management for this project. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Disclosures

Helen Pentikis is a paid consultant to Symbiomix Therapeutics. Carol Braun is a paid consultant to Symbiomix Therapeutics. Nikki Adetoro is an employee of Symbiomix Therapeutics.

Compliance with Ethics Guidelines

All study procedures were approved by an independent investigational review board (IRB) (Chesapeake IRB, Columbia, MD, USA). All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. All subjects provided written informed consent for participation prior to undergoing any study procedures.

References

  1. 1.
    Ravel J, Brotman RM, Gajer P, Ma B, Nandy M, Fadrosh DW, et al. Daily temporal dynamics of vaginal microbiota before, during and after episodes of bacterial vaginosis. Microbiome. 2013;1(1):29.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Sobel J. Bacterial vaginosis. In: Barbieri R, Vanessa A, editors. Up To Date. Waltham; 2012. Accessed 1 Sept 2015.Google Scholar
  3. 3.
    Marrazzo JM. Interpreting the epidemiology and natural history of bacterial vaginosis: are we still confused? Anaerobe. 2011;17(4):186–90.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Marrazzo JM, Thomas KK, Fiedler TL, Ringwood K, Fredricks DN. Relationship of specific vaginal bacteria and bacterial vaginosis treatment failure in women who have sex with women. Ann Intern Med. 2008;149(1):20–8.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Donders G. Diagnosis and management of bacterial vaginosis and other types of abnormal vaginal bacterial flora: a review. Obstet Gynecol Surv. 2010;65(7):462–73.CrossRefPubMedGoogle Scholar
  6. 6.
    Workowski KA, Berman S, Centers for Disease C, Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010;59(RR-12):1–110.Google Scholar
  7. 7.
    Gillis JC, Wiseman LR. Secnidazole. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic use in the management of protozoal infections and bacterial vaginosis. Drugs. 1996;51(4):621–38.CrossRefPubMedGoogle Scholar
  8. 8.
    Videau D, Niel G, Siboulet A, Catalan F. Secnidazole. A 5-nitroimidazole derivative with a long half-life. Br J Vener Dis 1978;54(2):77–80.Google Scholar
  9. 9.
    Hillier SL, Morgan FG, Waldbaum AS, Schwebke JR, Nyirjesy P, Adetoro N, Braun C. A phase 2 randomized, double-blind, placebo-controlled study to evaluate the effectiveness and safety of single, oral doses of SYM-1219, a granule formulation containing 1 and 2 gram doses of secnidazole, for the treatment of women with bacterial Vaginosis data presented at the 42nd Annual Meeting of the Infectious Disease Society of Obstetrics and Gynecology (IDSOG), Portland OR, August 6–8.Google Scholar
  10. 10.
    Pentikis H, Adetoro N, Braun C. A Phase I study to determine the single dose, safety, and pharmacokinetics of SYM-1219 (secnidazole) in healthy female volunteers. Abstract presented at ASCPT 2015 Annual Meeting, March 3–7 2015, New Orleans, LA; 2015.Google Scholar
  11. 11.
    Bartley JB, Ferris DG, Allmond LM, Dickman ED, Dias JK, Lambert J. Personal digital assistants used to document compliance of bacterial vaginosis treatment. Sex Transm Dis. 2004;31(8):488–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Cockburn J, Gibberd RW, Reid AL, Sanson-Fisher RW. Determinants of non-compliance with short term antibiotic regimens. Br Med J (Clin Res Ed). 1987;295(6602):814–8.CrossRefGoogle Scholar
  13. 13.
    Back DJ, Houlgrave R, Tjia JF, Ward S, Orme ML. Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes. J Steroid Biochem Mol Biol. 1991;38(2):219–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Guengerich FP. Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol. 1988;33(5):500–8.PubMedGoogle Scholar
  15. 15.
    Combined Nelson A, Contraceptives Oral. Contraceptive technology. 19th ed. New York: Ardent Media Inc; 2007. p. 193–270.Google Scholar
  16. 16.
    Lohr PA, Creinin MD. Oral contraceptives and breakthrough bleeding: what patients need to know. J Fam Pract. 2006;55(10):872–80.PubMedGoogle Scholar
  17. 17.
    Ortho-Novum [prescribing information]. Titusville: Janssen Pharmaceuticals, Inc.; 2009.Google Scholar
  18. 18.
    Davit B, Braddy AC, Conner DP, Yu LX. International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences. AAPS J. 2013;15(4):974–90.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;15(6):657–80.CrossRefPubMedGoogle Scholar
  20. 20.
    US Food and Drug Administration, (CDER). Guidance for industry: drug interaction studies: study design, data analysis, implications for dosing, and labeling recommendations. Clin Pharmacol. 2012;1–79.Google Scholar
  21. 21.
    Chatterton JR. Pharmacology of contraceptive steroids. Glob Libr Women’s Med. 2012. doi: 10.3843/GLOWM.10386.
  22. 22.
    Kuhnz W. Pharmacokinetics of the contraceptive steroids levonorgestrel and gestodene after single and multiple oral administration to women. Am J Obstet Gynecol. 1990;163(6 Pt 2):2120–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Orme ML, Back DJ, Breckenridge AM. Clinical pharmacokinetics of oral contraceptive steroids. Clin Pharmacokinet. 1983;8(2):95–136.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Healthcare 2016

Authors and Affiliations

  • Helen S. Pentikis
    • 1
  • Nikki Adetoro
    • 1
  • Carol J. Braun
    • 1
  1. 1.Symbiomix Therapeutics, LLCBaltimoreUSA

Personalised recommendations