Pharmacokinetics of UC781-loaded intravaginal ring segments in rabbits: a comparison of polymer matrices
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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.
KeywordsUC781 Microbicide Intravaginal ring Pharmacokinetics
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.
- 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.PubMedGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar