Pharmacokinetics of the protein microbicide 5P12-RANTES in sheep following single dose vaginal gel administration [PublishAheadOfPrint]

5P12-RANTES, a chemokine analogue that potently blocks the HIV CCR5 co-receptor, 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 (6.16 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 in sheep, 5P12-RANTES concentrations were measured in vaginal fluid, vaginal tissue and serum over a 96-h period. All gels showed non-Newtonian pseudoplastic behaviour, with high concentration gels exhibiting greater viscosity and cohesive structure. In in vitro release testing, >90% 5P12-RANTES was released from the low and intermediate gels after 72 h. For the high concentration gel, ~50% 5P12-RANTES was detected, attributed to protein denaturation during lyophilisation and/or subsequent solvation of the protein within the gel matrix. In sheep, 5P12-RANTES concentrations in vaginal fluid, tissue and serum increased in a dose dependent manner. Highest concentrations were measured in fluid (10⁵–10⁷ ng/mL) followed by tissue (10⁴–10⁶ ng/mL) – both several orders of magnitude above reported half maximal inhibitory concentrations – and lowest in serum (< 10² ng/mL). The 5P12-RANTES pharmacokinetic data is similar to that reported previously for other candidate microbicides. These data, coupled with 5P12-RANTES's picomolar potency, its strong barrier to resistance, and full protection observed in a rhesus macaque vaginal challenge model, support the continued development of 5P12-RANTES as a microbicide.

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