Pharmacokinetics of the Protein Microbicide 5P12-RANTES in Sheep following Single-Dose Vaginal Gel Administration.
| Autor: | McBride JW; School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom., Dias N; Envigo, Huntingdon, Cambridgeshire, United Kingdom., Cameron D; Envigo, Huntingdon, Cambridgeshire, United Kingdom., Offord RE; Mintaka Foundation for Medical Research, Geneva, Switzerland., Hartley O; Mintaka Foundation for Medical Research, Geneva, Switzerland.; Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland., Boyd P; School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom., Kett VL; School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom., Malcolm RK; School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom k.malcolm@qub.ac.uk. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2017 Sep 22; Vol. 61 (10). Date of Electronic Publication: 2017 Sep 22 (Print Publication: 2017). |
| DOI: | 10.1128/AAC.00965-17 |
| Abstrakt: | 5P12-RANTES, a chemokine analogue that potently blocks the HIV CCR5 coreceptor, is being developed as both a vaginal and rectal microbicide for prevention of sexual transmission of HIV. Here, we report the first pharmacokinetic data for 5P12-RANTES following single-dose vaginal gel administration in sheep. Aqueous gel formulations containing low (1.24-mg/ml), intermediate (6.18-mg/ml), and high (32.0-mg/ml; suspension-type gel) concentrations of 5P12-RANTES were assessed via rheology, syringeability, and in vitro release testing. Following vaginal gel administration to sheep, 5P12-RANTES concentrations were measured in vaginal fluid, vaginal tissue, and serum over a 96-h period. All gels showed non-Newtonian pseudoplastic behavior, with the high-concentration gels exhibiting a greater viscosity and cohesive structure than the intermediate- and low-concentration gels. In in vitro release testing, >90% 5P12-RANTES was released from the low- and intermediate-concentration gels after 72 h. For the high-concentration gel, ∼50% 5P12-RANTES was detected, attributed to protein denaturation during lyophilization and/or subsequent solvation of the protein within the gel matrix. In sheep, 5P12-RANTES concentrations in vaginal fluid, vaginal tissue, and serum increased in a dose-dependent manner. The highest concentrations were measured in vaginal fluid (10 5 to 10 7 ng/ml), followed by vaginal tissue (10 4 to 10 6 ng/ml). Both of these concentration ranges are several orders of magnitude above the reported half-maximal inhibitory concentrations. The lowest concentration was measured in serum (<10 2 ng/ml). The 5P12-RANTES pharmacokinetic data are similar to those reported previously for other candidate microbicides. These data, coupled with 5P12-RANTES's potency at picomolar concentrations, its strong barrier to resistance, and the full protection that it was observed to provide in a rhesus macaque vaginal challenge model, support the continued development of 5P12-RANTES as a microbicide. (Copyright © 2017 American Society for Microbiology.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|