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Pharmacokinetics of the Protein Microbicide 5P12-RANTES in Sheep following Single-Dose Vaginal Gel Administration

McBride, John W
Dias, Nicola
Cameron, David
Boyd, Peter
Kett, Vicky L
Malcolm, R Karl
Published in Antimicrobial Agents and Chemotherapy. 2017, vol. 61, no. 10
Abstract 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 (105 to 107 ng/ml), followed by vaginal tissue (104 to 106 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 (<102 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.
Keywords AdministrationIntravaginalAnimalsAnti-HIV Agents/pharmacokineticsCCR5 Receptor Antagonists/pharmacokineticsChemokinesCC/pharmacokineticsFemaleHIV Infections/drug therapyHIV-1/drug effectsSheepVaginal CreamsFoamsAnd Jellies/pharmacokinetics
PMID: 28784672
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Research group Hiv (835)
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MCBRIDE, John W et al. Pharmacokinetics of the Protein Microbicide 5P12-RANTES in Sheep following Single-Dose Vaginal Gel Administration. In: Antimicrobial Agents and Chemotherapy, 2017, vol. 61, n° 10. doi: 10.1128/AAC.00965-17 https://archive-ouverte.unige.ch/unige:112659

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Deposited on : 2019-01-09

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