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. 2012 Jan;56(1):103-9.
doi: 10.1128/AAC.00597-11. Epub 2011 Oct 10.

Pharmacokinetics of tenofovir following intravaginal and intrarectal administration of tenofovir gel to rhesus macaques

Jeremy Nuttall  1 , Angela Kashuba, Ruili Wang, Nicole White, Philip Allen, Jeffrey Roberts, Joseph Romano
Affiliations

Pharmacokinetics of tenofovir following intravaginal and intrarectal administration of tenofovir gel to rhesus macaques

Jeremy Nuttall et al. Antimicrob Agents Chemother. 2012 Jan.

Abstract

Tenofovir gel (1%) is being developed as a microbicide for the prevention of human immunodeficiency virus (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 simian-human immunodeficiency virus (SHIV), but very little pharmacokinetic information for 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 h after dosing, and at 24 h postdosing biopsy specimens 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 to 2 log units higher than those in the opposite compartment and 4 to 5 log units higher than those in plasma. Exposure in vaginal fluid after vaginal dosing was 58 to 82% lower than that in rectal fluid after rectal dosing, but plasma exposure was 1- to 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.

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Figures

Fig 1
Fig 1
Median concentrations (n = 6) of tenofovir in vaginal fluid (♦), rectal fluid (■), and blood plasma (▲) following intravaginal administration of 0.2% tenofovir gel (A), 1% tenofovir gel (B), and 5% tenofovir gel (C). Bars represent the 25th and 75th percentiles.
Fig 2
Fig 2
Dose relationship of AUC0–24 (■) and Cmax (♦) in vaginal fluid (A), rectal fluid (B), and blood plasma (C) following intravaginal administration of 0.2%, 1%, and 5% tenofovir gel. Values represent the medians for 6 macaques, with the 25th and 75th percentiles indicated by the bars.
Fig 3
Fig 3
Median concentrations (n = 6) of tenofovir in vaginal fluid (♦), rectal fluid (■), and blood plasma (▲) following intrarectal administration of 0.2% tenofovir gel (A), 1% tenofovir gel (B), and 5% tenofovir gel (C). Bars represent the 25th and 75th percentiles.
Fig 4
Fig 4
Dose relationship of AUC0–24 (■) and Cmax (♦) in vaginal fluid (A), rectal fluid (B), and blood plasma (C) following intrarectal administration of 0.2%, 1%, and 5% tenofovir gel. Values represent the medians for 6 macaques, with the 25th and 75th percentiles indicated by the bars.
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