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Pharmacokinetics of UC781-loaded intravaginal ring segments in rabbits: a comparison of polymer matrices

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Abstract

UC781 is a potent and poorly water-soluble nonnucleoside reverse transcriptase inhibitor being investigated as a potential microbicide for preventing sexual transmission of HIV-1. This study was designed to evaluate the in vivo release and pharmacokinetics of UC781 delivered from matrix-type intravaginal ring segments in rabbits. Three polymer matrices (polyurethane, ethylene vinyl acetate copolymer, and silicone elastomer) and two drug loadings (5 and 15 mg/segment) were evaluated in at least one of two independent studies for up to 28 days in vivo. Inter-study comparison of in vivo release, vaginal tissue, and plasma concentrations for similar formulations demonstrated good reproducibility of the animal model. Mean estimates for a 28-day in vivo release ranged from 0.35 to 3.17 mg UC781 per segment. Mean proximal vaginal tissue levels (adjacent to the IVR segment) were 8–410 ng/g and did not change significantly with time for most formulations. Distal vaginal tissue levels of UC781 were 6- to 49-fold lower than proximal tissue levels. Mean UC781 plasma levels were low for all formulations, at 0.09–0.58 ng/mL. All formulations resulted in similar UC781 concentrations in vaginal tissue and plasma, except the low loading polyurethane group which provided significantly lower levels. Loading dependent release and pharmacokinetics were only clearly observed for the polyurethane matrix. Based on these results, intravaginal ring segments loaded with UC781 led to vaginal tissue concentrations ranging from below to approximately two orders of magnitude higher than UC781’s EC50 under in vitro conditions (2.8 ng/mL), with little influence by polymer matrix or UC781 loading. Moreover, these findings support the use of rabbit vaginal pharmacokinetic studies in preclinical testing of microbicide intravaginal rings.

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References

  1. Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329(5996):1168–74.

    Article  PubMed  CAS  Google Scholar 

  2. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587–99.

    Article  PubMed  CAS  Google Scholar 

  3. Balzarini J, Naesens L, Verbeken E, Laga M, Van Damme L, Parniak M, et al. Preclinical studies on thiocarboxanilide UC-781 as a virucidal agent. AIDS. 1998;12(10):1129–38.

    Article  PubMed  CAS  Google Scholar 

  4. Balzarini J, Brouwer WG, Dao DC, Osika EM, De Clercq E. Identification of novel thiocarboxanilide derivatives that suppress a variety of drug-resistant mutant human immunodeficiency virus type 1 strains at a potency similar to that for wild-type virus. Antimicrob Agents Chemother. 1996;40(6):1454–66.

    PubMed  CAS  Google Scholar 

  5. Borkow G, Arion D, Wainberg MA, Parniak MA. The thiocarboxanilide nonnucleoside inhibitor UC781 restores antiviral activity of 3′-azido-3′-deoxythymidine (AZT) against AZT-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. 1999;43(2):259–63.

    PubMed  CAS  Google Scholar 

  6. Pelemans H, Esnouf R, De Clercq E, Balzarini J. Mutational analysis of trp-229 of human immunodeficiency virus type 1 reverse transcriptase (RT) identifies this amino acid residue as a prime target for the rational design of new non-nucleoside RT inhibitors. Mol Pharmacol. 2000;57(5):954–60.

    PubMed  CAS  Google Scholar 

  7. Van Herrewege Y, Michiels J, Van Roey J, Fransen K, Kestens L, Balzarini J, et al. In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother. 2004;48(1):337–9.

    Article  PubMed  Google Scholar 

  8. Zussman A, Lara L, Lara HH, Bentwich Z, Borkow G. Blocking of cell-free and cell-associated HIV-1 transmission through human cervix organ culture with UC781. AIDS. 2003;17(5):653–61.

    Article  PubMed  CAS  Google Scholar 

  9. Fletcher P, Kiselyeva Y, Wallace G, Romano J, Griffin G, Margolis L, et al. The nonnucleoside reverse transcriptase inhibitor UC-781 inhibits human immunodeficiency virus type 1 infection of human cervical tissue and dissemination by migratory cells. J Virol. 2005;79(17):11179–86.

    Article  PubMed  CAS  Google Scholar 

  10. Borkow G, Barnard J, Nguyen TM, Belmonte A, Wainberg MA, Parniak MA. Chemical barriers to human immunodeficiency virus type 1 (HIV-1) infection: retrovirucidal activity of UC781, a thiocarboxanilide nonnucleoside inhibitor of HIV-1 reverse transcriptase. J Virol. 1997;71(4):3023–30.

    PubMed  CAS  Google Scholar 

  11. Schwartz JL, Kovalevsky G, Lai JJ, Ballagh SA, McCormick T, Douville K, et al. A randomized six-day safety study of an antiretroviral microbicide candidate UC781, a non-nucleoside reverse transcriptase inhibitor. Sex Transm Dis. 2008;35(4):414–9.

    Article  PubMed  CAS  Google Scholar 

  12. Clark M, McCormick T, Doncel G, Friend D. Preclinical evaluation of UC781 microbicide vaginal drug delivery. Drug Delivery and Translational Research. 2011;1(2):175–82.

    Article  CAS  Google Scholar 

  13. Ahrendt HJ, Nisand I, Bastianelli C, Gomez MA, Gemzell-Danielsson K, Urdl W, et al. Efficacy, acceptability and tolerability of the combined contraceptive ring, NuvaRing, compared with an oral contraceptive containing 30 microg of ethinyl estradiol and 3 mg of drospirenone. Contraception. 2006;74(6):451–7.

    Article  PubMed  CAS  Google Scholar 

  14. Novak A, de la Loge C, Abetz L, van der Meulen EA. The combined contraceptive vaginal ring, NuvaRing: an international study of user acceptability. Contraception. 2003;67(3):187–94.

    Article  PubMed  CAS  Google Scholar 

  15. Henriksson L, Stjernquist M, Boquist L, Cedergren I, Selinus I. A one-year multicenter study of efficacy and safety of a continuous, low-dose, estradiol-releasing vaginal ring (Estring) in postmenopausal women with symptoms and signs of urogenital aging. Am J Obstet Gynecol. 1996;174(1 Pt 1):85–92.

    Article  PubMed  CAS  Google Scholar 

  16. Nel A, Smythe S, Young K, Malcolm K, McCoy C, Rosenberg Z, et al. Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women. J Acquir Immune Defic Syndr. 2009;51(4):416–23.

    Article  PubMed  CAS  Google Scholar 

  17. Gupta KM, Pearce SM, Poursaid AE, Aliyar HA, Tresco PA, Mitchnik MA, et al. Polyurethane intravaginal ring for controlled delivery of dapivirine, a nonnucleoside reverse transcriptase inhibitor of HIV-1. J Pharm Sci. 2008;97(10):4228–39.

    Article  PubMed  CAS  Google Scholar 

  18. Johnson TJ, Gupta KM, Fabian J, Albright TH, Kiser PF. Segmented polyurethane intravaginal rings for the sustained combined delivery of antiretroviral agents dapivirine and tenofovir. Eur J Pharm Sci. 2010;39(4):203–12.

    Article  PubMed  CAS  Google Scholar 

  19. Fetherston SM, Malcolm RK, Woolfson AD. Controlled-release vaginal ring drug-delivery systems: a key strategy for the development of effective HIV microbicides. Therapeutic Delivery. 2010;1:785–802.

    Article  CAS  Google Scholar 

  20. Woolfson AD, Malcolm RK, Toner CF, Morrow RJ, Lowry D, Jamil A, et al. Potential use of vaginal rings for prevention of heterosexual transmission of HIV: a controlled-release strategy for HIV microbicides. American Journal of Drug Delivery. 2006;4(1):7–20.

    Article  CAS  Google Scholar 

  21. Malcolm K, Woolfson D, Russell J, Tallon P, McAuley L, Craig D. Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings. J Control Release. 2003;90(2):217–25.

    Article  PubMed  CAS  Google Scholar 

  22. Chien YW, Mares SE, Berg J, Huber S, Lambert HJ, King KF. Controlled drug release from polymeric delivery devices. III: In vitro–in vivo correlation for intravaginal release of ethynodiol diacetate from silicone devices in rabbits. J Pharm Sci. 1975;64(11):1776–81.

    Article  PubMed  CAS  Google Scholar 

  23. Damian F, Blaton N, Naesens L, Balzarini J, Kinget R, Augustijns P, et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur J Pharm Sci. 2000;10(4):311–22.

    Article  PubMed  CAS  Google Scholar 

  24. Doncel GF, Clark MR. Preclinical evaluation of anti-HIV microbicide products: new models and biomarkers. Antivir Res. 2010;88 Suppl 1:S10–8.

    Article  PubMed  CAS  Google Scholar 

  25. Barberini F, Correr S, De Santis F, Motta PM. The epithelium of the rabbit vagina: a microtopographical study by light, transmission and scanning electron microscopy. Arch Histol Cytol. 1991;54(4):365–78.

    Article  PubMed  CAS  Google Scholar 

  26. Barberini F, De Santis F, Correr S, Motta PM. The mucosa of the rabbit vagina: a proposed experimental model for correlated morphofunctional studies in humans. Eur J Obstet Gynecol Reprod Biol. 1992;44(3):221–7.

    Article  PubMed  CAS  Google Scholar 

  27. Rodriguez-Antolin J, Xelhuantzi N, Garcia-Lorenzana M, Cuevas E, Hudson R, Martinez-Gomez M. General tissue characteristics of the lower urethral and vaginal walls in the domestic rabbit. Int Urogynecol J Pelvic Floor Dysfunct. 2009;20(1):53–60.

    Article  PubMed  Google Scholar 

  28. Chien YW, Lambert HJ. Controlled drug release from polymeric delivery devices. II. Differentiation between partition-controlled and matrix-controlled drug release mechanisms. J Pharm Sci. 1974;63(4):515–9.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The support of Missy Peet and Devon Kyle of MPI Research, Inc., in coordination of the rabbit studies and sample bioanalytical analysis, is gratefully acknowledged. This work was funded by the United States Agency for International Development (USAID) under Cooperative Agreement GPO-A-00-08-00005-00. The views of the authors do not necessarily reflect those of USAID.

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Author notes

  1. Christopher McConville

    Present address: School of Pharmacy, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, WA, 6845, Australia

Authors and Affiliations

  1. CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, 1911 North Fort Myer Drive, Suite 900, Arlington, VA, 22209, USA

    Meredith R. Clark & David R. Friend

  2. Department of Bioengineering, University of Utah, 20 S 2030 E, Room 108, Salt Lake City, UT, 84112, USA

    Patrick F. Kiser

  3. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84112, USA

    Patrick F. Kiser

  4. Particle Sciences Inc., 3894 Courtney St, #180, Bethlehem, PA, 18017, USA

    Andrew Loxley

  5. School of Pharmacy, Medical Biology Centre, Queen’s University of Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK

    Christopher McConville & R. Karl Malcolm

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  1. Meredith R. Clark
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  2. Patrick F. Kiser
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Correspondence to Meredith R. Clark.

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Clark, M.R., Kiser, P.F., Loxley, A. et al. Pharmacokinetics of UC781-loaded intravaginal ring segments in rabbits: a comparison of polymer matrices. Drug Deliv. and Transl. Res. 1, 238–246 (2011). https://doi.org/10.1007/s13346-011-0032-4

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