Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques.
Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques.
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DOI：
10.1093/jac/dks422
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发表时间：
2013-03
期刊：
影响因子：
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通讯作者：
R. Malcolm;Claire J. Forbes;L. Geer;R. Veazey;L. Goldman;P. Klasse;John P. Moore
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文献类型：
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作者：
R. Malcolm;Claire J. Forbes;L. Geer;R. Veazey;L. Goldman;P. Klasse;John P. Moore
目的研究马拉韦罗（一种CCR 5靶向HIV-1进入抑制剂）在恒河猴中阴道给药各种马拉韦罗载水羟乙基纤维素（HEC）凝胶后的药代动力学（PK），并将PK数据与单次高剂量阴道SHIV-162 P3攻击模型中的疗效相关联。方法在阴道单次施用各种马拉韦罗负载的HEC凝胶后72小时内评估阴道液（Weck-Cel（®）海绵）、阴道组织（穿刺活检）和血浆中马拉韦罗的浓度。马拉韦罗凝胶浓度的范围足够宽（0.003%-3.3%w/w），试验凝胶包括完全溶解和主要分散的制剂。还测量了HEC凝胶对单次高剂量阴道SHIV-162 P3攻击的功效，并与PK浓度相关。结果马拉韦罗在阴道液（范围10（4）-10（7）ng/mL）、阴道组织（100-1200 ng/g）和血浆（<10（2）ng/mL）中的浓度高度依赖于马拉韦罗凝胶载量，与凝胶中马拉韦罗组分的形式无关（溶解与分散）。液体和血浆浓度通常在凝胶应用后0.5或2小时最高，然后稳定下降至72小时。马拉韦罗在各种生物区室中的浓度与对阴道SHIV-162 P3攻击的保护程度密切相关。使用3.3% w/w马拉韦罗凝胶实现完全保护。结论：观察到PK和疗效之间高度相关。根据3.3% w/w马拉韦罗凝胶获得的数据，需要将阴道液和组织水平分别维持在10（7）ng/mL和10（3）ng/g左右，才能获得该化合物的完全保护。
OBJECTIVES To investigate the pharmacokinetics (PK) of maraviroc, a CCR5-targeted HIV-1 entry inhibitor, in rhesus macaques following vaginal administration of various maraviroc-loaded aqueous hydroxyethylcellulose (HEC) gels, and to correlate the PK data with efficacy in a single high-dose vaginal SHIV-162P3 challenge model. METHODS Maraviroc concentrations in vaginal fluid (Weck-Cel(®) sponge), vaginal tissue (punch biopsy) and plasma were assessed over 72 h following single-dose vaginal application of various maraviroc-loaded HEC gels. The range of maraviroc gel concentrations was sufficiently broad (0.003%-3.3% w/w) that test gels included both fully solubilized and predominantly dispersed formulations. The efficacy of the HEC gels against a single high-dose vaginal SHIV-162P3 challenge was also measured, and correlated with the PK concentrations. RESULTS Maraviroc concentrations in vaginal fluid (range 10(4)-10(7) ng/mL), vaginal tissue (100-1200 ng/g) and plasma (<10(2) ng/mL) were highly dependent on maraviroc gel loading, irrespective of the form of the maraviroc component within the gel (solubilized versus dispersed). Fluid and plasma concentrations were generally highest 0.5 or 2 h after gel application, before declining steadily through to 72 h. Maraviroc concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV-162P3 challenge. Complete protection was achieved with a 3.3% w/w maraviroc gel. CONCLUSIONS A high degree of correlation between PK and efficacy was observed. Based on the data obtained with the 3.3% w/w maraviroc gel, maintenance of vaginal fluid and tissue levels in the order of 10(7) ng/mL and 10(3) ng/g, respectively, are required for complete protection with this compound.