多替拉韦在 HIV 阴性男性单次及多次给药后在生殖道和直肠中的药代动力学。
Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing.
机构信息
University of North Carolina at Chapel Hill Eshelman School of Pharmacy, Chapel Hill, NC, USA.
出版信息
J Acquir Immune Defic Syndr. 2013 Sep 1;64(1):39-44. doi: 10.1097/QAI.0b013e31829ed7a4.
OBJECTIVES
To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men.
DESIGN
A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days.
METHODS
Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3.
RESULTS
BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and ∼2-fold greater than the PA-IC90. RF AUCs were ∼2%-5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT.
CONCLUSIONS
DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained ∼2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.
目的
描述健康 HIV 阴性男性单次及稳态时多替拉韦（DTG）在血浆（BP）、精液（SF）、结直肠组织（RT）和直肠黏膜液（RF）中的药代动力学（PK）。
设计
一项开放标签的 1 期 PK 研究，招募了 12 名每日服用 50mg DTG 连续 8 天的健康男性志愿者。
方法
在首次（PK1）和多次（PK2）给药后 24 小时内采集了 11 对 BP 样本和 3 对 SF 和 RF 样本。在 PK1 和 PK2 时，在 6 个时间点中的 1 个时间点采集 RT 活检样本，以生成复合 PK 图谱。通过验证的液相色谱-串联质谱法（LC-MS/MS）分析 DTG 浓度。使用 Phoenix WinNonlin v6.3 进行非房室 PK 分析，并使用 SAS v9.3 确定 Spearman 秩相关系数。
结果
BP 的 AUC 与之前的报道相似，24 小时时浓度（C24 h）比 64ng/ml 蛋白校正 90%病毒抑制浓度（PA-IC90）高 6-34 倍。SF 中的暴露量<BP 的 7%，低于 PA-IC90。RT 的暴露量是 BP 的 17%，约为 PA-IC90 的 2 倍。RF 的 AUC 约为 RT 的 2%-5%，与 RT 无相关性（rho=0.43，P=0.17）。在 BP、SF 和 RT 中观察到 DTG 多次给药后的蓄积。
结论
DTG 的 BP PK 与之前的发表值一致。SF 中的浓度<BP 的 7%，SF 的 C24 h 低于 PA-IC90。然而，SF 中的蛋白结合尚未测量。尽管 RT 中的 DTG AUC 低于 BP 的 20%，但 RT 的 C24 h 仍约为 PA-IC90 的 2 倍。RF 不是 RT 浓度的可靠替代物。
Zotero 插件