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首页> 外文期刊>International Journal of Pharmaceutics >Vaginal tamoxifen for treatment of vulvar and vaginal atrophy: Pharmacokinetics and local tolerance in a rabbit model over 28 days
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Vaginal tamoxifen for treatment of vulvar and vaginal atrophy: Pharmacokinetics and local tolerance in a rabbit model over 28 days

机译：用于治疗外阴和阴道萎缩的阴道三肟：28天的兔模型中的药代动力学和局部耐受性

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Vaginally delivered tamoxifen is being developed as alternative to estrogen-based therapies for the treatment of vulvar and vaginal atrophy (VVA) symptoms in subjects at high risk for breast cancer, undergoing treatment for breast cancer with aromatase inhibitors or are breast cancer survivors. Tamoxifen (1 or 20 mg) was administered intra-vaginally to female rabbits once-daily over a 28-day period to assess its pharmacokinetics, systemic exposure and local vaginal tolerance. Plasma samples were taken to assess concentrations of tamoxifen and its metabolites 4-hydroxytamoxifen and N-desmethyltamoxifen over the first day of vaginal administration and following the last dose on Day 28. In-life observations included evaluation of the vaginal region for signs of irritation. At necropsy, vaginal irritation was assessed by the method of Eckstein which reflect collective histopathological grading of four parameters within the vagina including epithelial morphology, leukocytic infiltration, congestion, and edema. Uterine effects of vaginal tamoxifen were also assessed. Plasma concentrations of tamoxifen were higher following administration of 20 mg tamoxifen compared to 1 mg tamoxifen at both Day 1 and Day 28. The metabolite 4-hydroxytamoxifen could not be detected on Day 1 and concentrations were low at Day 28 at the 1 mg tamoxifen dose. 4-Hydroxytamoxifen concentrations were low, but detectable at Day 1 and 28 following administration of 20 mg tamoxifen. The metabolite N-desmethyltamoxifen was undetectable at the 1 mg and 20 mg doses on Day 1; it remained undetectable at the 1 mg tamoxifen dose at Day 28. N-desmethyltamoxifen was detected over the first 8 h of Day 28 then fell below the quantitation limits. There was little to no vaginal or systemic accumulation of tamoxifen following once-daily dosing for 28 days. Tamoxifen accounted for more than 85% of the total systemic exposure compared to its metabolites, 4-hydroxytamoxifen, and N-desmethyltamoxifen. There was essentially no detectable vaginal irritation evident over the course of the study. At necropsy the individual Eckstein scores (maximum score of 16) of the proximal, mid, and distal vagina of females in the 1 mg and 20 mg dose groups were generally comparable in both groups and ranged from minimal to mild magnitude (1 mg dose group: ranging from 1 to 3 in the proximal vagina, 4 to 5 in the mid vagina, and 3 to 7 in the distal vagina; 20 mg dose group: ranging from 3 to 5 in the proximal vagina, 4 to 7 in the mid vagina, and 4 to 5 in the distal vagina). Overall, tamoxifen was absorbed and metabolized following vaginal administration and vaginal irritation was minimal to none at both doses.
机译：正在制定阴道递送的毒素作为雌激素的疗法治疗受试者治疗乳腺癌高风险的外阴和阴道萎缩（VVA）症状的替代疗法，正在接受患有芳香酶抑制剂的乳腺癌或乳腺癌幸存者的治疗。 Tamoxifen（1或20mg）在28天的时间内每天均匀地向雌性兔给予雌性兔，以评估其药代动力学，全身暴露和局部阴道耐受性。在阴道给药的第一天和第28天的最后剂量后，采取血浆样品来评估三莫昔芬及其代谢物4-羟基氧基毒素和N- desmethylylamoxifen的浓度。生活中的观察结果包括评估阴道区域的刺激迹象。在尸检时，通过Eckstein的方法评估阴道刺激，反映了阴道内的四个参数的集体组织病理学分级，包括上皮形态，白细胞浸润，充血和水肿。还评估了阴道三莫昔芬的子宫作用。在第1天和第28天的1mg Tamoxifen相比，施用20mg三莫昔芬的血浆浓度较高。在第1天和第28天，在第1天不能检测到代谢物4-羟基氧毒素，并且在1mg Tamoxifen剂量的第28天浓度低至。 4-羟基氧基氧浓度低，但在施用20mg三氧肟后的第1天和第28天可检测。在第1天，在1mg和20mg剂量上未检测到代谢物N-去甲基三甲酰嘧啶;在第28天的1mg Tamoxifen剂量下，它保持不可检测。在第28天的前8小时内检测到N-Desmethylamoxifen，然后低于定量限制。每日给药后28天持续几乎没有阴道或西昔芬的阴道或全身积累。与其代谢产物，4-羟基氧基毒素和N-去甲基三甲胺酸相比，Tamoxifen占全身暴露总体暴露的85％以上。在研究过程中基本上没有可检测的阴道刺激。在尸检时，在1mg和20mg剂量基团中近端，中间和远侧阴道的个体Eckstein评分（最高分数为16），两组通常相当，并且从最小程度到轻微的幅度（1mg剂量组：在近端阴道中的1至3位，中阴道中的4至5，远端阴道中的3至7; 20毫克剂量组：在近端阴道中的3至5分，在阴道中的4至7次和远端阴道中的4至5个）。总的来说，在阴道给药后吸收并代谢，阴道刺激在两种剂量下都是最小的。

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