The Clinical Pharmacokinetics of Lu AA21004 and its Major Metabolite in Healthy Young Volunteers
The Clinical Pharmacokinetics of Lu AA21004 and its Major Metabolite in Healthy Young Volunteers
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DOI：
10.1111/j.1742-7843.2012.00886.x
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发表时间：
2012-09-01
影响因子：
3.1
通讯作者：
Hojer, Astrid-Maria
中科院分区：
文献类型：
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作者：
Areberg, Johan;Sogaard, Birgitte;Hojer, Astrid-Maria
Lu AA21004是一种新型多模抗抑郁药，目前处于第三阶段开发。本报告的目的是详细介绍鲁AA21004及其主要非活性代谢物鲁AA34443((3-methyl-4-(2-piperazine-1-yl-phenylsulfanyl)-benzoic酸)在18岁至53岁健康男性和女性中的临床药代动力学。纳入2个单剂和1个多剂量研究的数据，志愿者总数为97人(，男，女33人)。术后采血、尿标本。和静脉注射。采用验证法测定鹿茸AA21004和鹿茸AA34443的含量。标准药动学参数采用非房室分析方法估算。绝对生物利用度为75%。口服后，鲁AA21004的吸收相延长，清除量适中，分布体积大，Tmax较晚，平均消除半衰期为57，与HR相似。在所研究的剂量范围内，Lu AA21004的暴露剂量与剂量呈线性关系(最高75毫克单次给药和60毫克多次给药)。体重校正后，鲁AA21004和鲁AA34443的暴露在男性和女性之间没有差异。Lu AA21004的肾清除量可忽略不计。主要代谢产物鲁AA34443的半衰期与鲁AA21004相似，但稳态时的蓄积率较低，为限速消除。综上所述，鲁AA21004具有较长的吸收相、中等的清除量和较大的分布体积。
Lu AA21004 is a novel multimodal antidepressant that is currently in phase 3 development. The objective of this report was to detail the clinical pharmacokinetics of Lu AA21004 and its major but inactive metabolite Lu AA34443 (3-methyl-4-(2-piperazine-1-yl-phenylsulfanyl)-benzoic acid) in healthy men and women aged between 18 and 53 similar to years. Data from two single-dose and one multiple-dose study were combined; the total number of volunteers was 97 (64 men, 33 women). Blood and urine samples were collected after p.o. and i.v. administrations to determine the content of Lu AA21004 and Lu AA34443 performed with a validated method. Standard pharmacokinetic parameters were estimated with non-compartmental analysis. The absolute bioavailability was 75%. After oral administration, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution resulting in late tmax values and a mean elimination half-life of 57 similar to hr. The exposure of Lu AA21004 showed a linear relationship with dose in the dose ranges studied (up to 75-mg single dosing and 60-mg multiple dosing). After weight correction, no differences in exposure for Lu AA21004 and Lu AA34443 were observed between men and women. The renal clearance of Lu AA21004 was negligible. The major metabolite Lu AA34443 had a half-life similar to that of Lu AA21004 but a lower accumulation ratio at steady-state, indicating formation-rate-limited elimination. In conclusion, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution.