Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring
Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring
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DOI：
10.1093/jac/dks151
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发表时间：
2012-08-01
影响因子：
5.2
通讯作者：
Herold, B. C.
中科院分区：
文献类型：
--
作者：
Keller, M. J.;Malone, A. M.;Herold, B. C.
全身应用阿昔洛韦及其前药伐昔洛韦可有效治疗和减少生殖器单纯疱疹病毒（HSV）的复发，减少传播。局部阿昔洛韦给药，如果它可以达到和维持相当的细胞内生殖道水平，可能是同样有效的治疗和抑制生殖器HSV。阿昔洛韦阴道环（IVR）给药可提供暴露前预防HSVacquisition.Tolerability和药代动力学进行了评估，在6个HIV阴性的女性生殖器复发性HSV谁改变了他们的日常口服伐昔洛韦抑制阿昔洛韦IVR 7天（n 3）或14天（n 3）。在口服和IVR给药后收集血液和宫颈阴道灌洗（CVL）以测量阿昔洛韦浓度，并获得生殖器拭子以通过PCR定量HSV脱落。口服伐昔洛韦后1218 h，中位血浆阿昔洛韦浓度为110.2 ng/mL（IQR，85.9233.5）。IVR给药后，血浆中几乎未检测到药物。口服伐昔洛韦后2小时，口服伐昔洛韦后1218小时，口服伐昔洛韦后154.4 ng/mL（60.7327.5），7天后438 ng/mL（178.5618.5）和14天后393 ng/mL（31.61615）的中位（IQR）CVL阿昔洛韦水平分别为127.3 ng/mL（21660.8）和393 ng/mL（31.61615）。口服给药后2小时的中位CVL阿昔洛韦水平与环使用后7天（P 0.99）和14天（P 0.75）观察到的水平相似。生殖器拭子中未检测到HSV DNA，炎症介质也无显著变化。这项首次人体研究表明，IVR可安全地递送粘膜水平的阿昔洛韦，与口服伐昔洛韦相似，而不会全身吸收。需要进行更深入的位点特异性药代动力学研究，以确定是否需要更高的局部浓度以实现生殖道内的最佳药物分布。
Systemic aciclovir and its prodrug valaciclovir are effective in treating and reducing recurrences of genital herpes simplex virus (HSV) and reducing transmission. Local aciclovir delivery, if it can achieve and maintain comparable intracellular genital tract levels, may be equally effective in the treatment and suppression of genital HSV. Intravaginal ring (IVR) delivery of aciclovir may provide pre-exposure prophylaxis against HSV acquisition.Tolerability and pharmacokinetics were evaluated in six HIV-negative women with recurrent genital HSV who switched their daily oral valaciclovir suppression to an aciclovir IVR for 7 days (n3) or 14 days (n3). Blood and cervicovaginal lavage (CVL) were collected after oral and IVR dosing to measure aciclovir concentrations and genital swabs were obtained to quantify HSV shedding by PCR.The rings were well tolerated. Median plasma aciclovir concentrations were 110.2 ng/mL (IQR, 85.9233.5) 1218 h after oral valaciclovir. Little or no drug was detected in plasma following IVR dosing. Median (IQR) CVL aciclovir levels were 127.3 ng/mL (21660.8) 2 h after oral valaciclovir, 154.4 ng/mL (60.7327.5) 1218 h after oral valaciclovir and 438 ng/mL (178.5618.5) after 7 days and 393 ng/mL (31.61615) after 14 days of aciclovir ring use. Median CVL aciclovir levels 2 h after oral dosing were similar to levels observed 7 (P0.99) and 14 (P0.75) days after ring use. HSV DNA was not detected in genital swabs and there was no significant change in inflammatory mediators.This first-in-human study demonstrated that an IVR could safely deliver mucosal levels of aciclovir similar to oral valaciclovir without systemic absorption. More intensive site-specific pharmacokinetic studies are needed to determine whether higher local concentrations are needed to achieve optimal drug distribution within the genital tract.