International Partnership for Microbicides, Silver Spring, Maryland, USA.
Antimicrob Agents Chemother. 2012 Jan;56(1):103-9. doi: 10.1128/AAC.00597-11. Epub 2011 Oct 10.
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.
替诺福韦凝胶（1%）正在开发作为一种用于预防人类免疫缺陷病毒（HIV）感染的杀微生物剂，已显示可将女性的传播风险降低 39%。该凝胶在应用于阴道或直肠之前，通过阴道内或直肠内应用，也可以预防恒河猴感染猴免疫缺陷病毒（SHIV），但很少有关于恒河猴的药代动力学信息可以帮助推断数据到人类身上，并为未来的发展活动提供信息。我们已经确定了在阴道和直肠内给予 0.2%、1%和 5%凝胶后，替诺福韦在恒河猴体内的药代动力学。在给药后 24 小时内采集血浆和阴道及直肠液样本，并在给药后 24 小时从阴道壁、宫颈和直肠采集活检样本。阴道和直肠给药后，替诺福韦迅速分布到给药部位以外的基质中。在所有基质中，随着剂量的增加，暴露量增加，并且使用 1%和 5%制剂时，在大多数动物中，在给药后 24 小时仍可检测到浓度。在所有剂量下，给药部位的浓度通常比相反隔室中的浓度高 1 到 2 个对数单位，比血浆中的浓度高 4 到 5 个对数单位。阴道给药后阴道液中的暴露量比直肠给药后直肠液中的暴露量低 58%至 82%，但阴道给药后的血浆暴露量比直肠给药后的血浆暴露量高 1 到 2 倍。这些数据表明，替诺福韦为基础的杀微生物剂可能具有保护作用，无论杀微生物剂是阴道内应用还是直肠内应用，都可以通过阴道或肛门性交进行接触。
