via AAC Accepts, by Jeremy Nuttall, Angela Kashuba, Ruili Wang, Nicole White, Philip Allen, Jeffrey Roberts, and Joseph Romano
Abstract
Tenofovir gel (1%) is being developed as a microbicide for the prevention of HIV infection, and has been shown to reduce transmission to women by 39%. The gel also prevents infection in macaques when applied intravaginally or intrarectally prior to challenge with SHIV, but very little pharmacokinetic information in macaques is available to help extrapolate the data to humans, and thus inform future development activities. We have determined the pharmacokinetics of tenofovir in macaques following intravaginal and intrarectal administration of 0.2, 1 and 5% gels. Plasma and vaginal and rectal fluid samples were collected up to 24 hours after dosing, and at 24 hours post dosing biopsies were taken from the vaginal wall, cervix and rectum. Following vaginal and rectal administration, tenofovir rapidly distributed to the matrices distal to the site of administration. In all matrices, exposure increased with increasing dose, and with the 1% and 5% formulations, concentrations remained detectable in most animals 24 h after dosing. At all doses, concentrations at the dosing site were typically 1-2 logs higher than in the opposite compartment, and 4-5 logs higher than in plasma. Exposure in vaginal fluid after vaginal dosing was 58-82% lower than in rectal fluid after rectal dosing, but plasma exposure was 1-2-fold greater after vaginal dosing than after rectal dosing. These data suggest that a tenofovir-based microbicide may have the potential to protect when exposure is via vaginal or anal intercourse, regardless of whether the microbicide is applied vaginally or rectally.
[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]
Abstract
Tenofovir gel (1%) is being developed as a microbicide for the prevention of HIV infection, and has been shown to reduce transmission to women by 39%. The gel also prevents infection in macaques when applied intravaginally or intrarectally prior to challenge with SHIV, but very little pharmacokinetic information in macaques is available to help extrapolate the data to humans, and thus inform future development activities. We have determined the pharmacokinetics of tenofovir in macaques following intravaginal and intrarectal administration of 0.2, 1 and 5% gels. Plasma and vaginal and rectal fluid samples were collected up to 24 hours after dosing, and at 24 hours post dosing biopsies were taken from the vaginal wall, cervix and rectum. Following vaginal and rectal administration, tenofovir rapidly distributed to the matrices distal to the site of administration. In all matrices, exposure increased with increasing dose, and with the 1% and 5% formulations, concentrations remained detectable in most animals 24 h after dosing. At all doses, concentrations at the dosing site were typically 1-2 logs higher than in the opposite compartment, and 4-5 logs higher than in plasma. Exposure in vaginal fluid after vaginal dosing was 58-82% lower than in rectal fluid after rectal dosing, but plasma exposure was 1-2-fold greater after vaginal dosing than after rectal dosing. These data suggest that a tenofovir-based microbicide may have the potential to protect when exposure is via vaginal or anal intercourse, regardless of whether the microbicide is applied vaginally or rectally.
[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]
