Pharmacokinetics and Safety of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor, in Healthy Volunteers
Pharmacokinetics and Safety of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor, in Healthy Volunteers
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DOI：
10.1128/aac.00842-09
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发表时间：
2010-01-01
影响因子：
4.9
通讯作者：
Piscitelli, Stephen C.
中科院分区：
文献类型：
--
作者：
Min, Sherene;Song, Ivy;Piscitelli, Stephen C.
S/GSK 1349572是一种新型整合酶抑制剂，具有强效体外抗HIV活性、不同于其他整合酶抑制剂的体外耐药特征以及良好的临床前安全性和药代动力学（PK）。一项随机、双盲、安慰剂对照、单次给药和多次给药、剂量递增研究在健康受试者中评价了S/GSK 1349572的PK、安全性和耐受性。在单次给药研究中，两个队列各10例受试者（8例活性药物，2例接受安慰剂）以交替组设计接受2、5、10、25、50和100 mg混悬液给药。在多次给药研究中，3个队列各10例受试者（8例活性药物，2例接受安慰剂）接受10、25和50 mg混悬液给药，每日一次，持续10天。使用25 mg剂量进行了咪达唑仑的细胞色素P450 3A（CYP 3A）子研究。定期进行实验室检查、生命体征、心电图（ECG）和PK采样。S/GSK 1349572耐受性良好。大多数不良事件（AE）为轻度，报告了少数中度AE。头痛是最常见的AE。未观察到具有临床意义的实验室趋势或ECG变化。PK在研究的剂量范围内呈线性。给药间隔内浓度-时间曲线下面积的稳态几何平均值（AUC（0-tau））和血浆中药物的最大浓度（C-max）范围为16.7 μ g。h/ml（变异系数[CV]，15%）和1.5 μ g/ml（CV，24%）（10 mg剂量至76.8 μ g）。h/ml（CV，19%）和6.2 μ g/ml（CV，15%）。50 mg剂量给药间隔结束时的几何平均稳态浓度（C-tau）为1.6 μ g/ml，约为蛋白质校正的90%抑制浓度（0.064 μ g/ml）的25倍。半衰期约为15 h。S/GSK 1349572对咪达唑仑暴露量无影响，表明其不调节CYP 3A活性。PK特征表明，每日一次低mg剂量将达到治疗浓度。
S/GSK1349572 is a novel integrase inhibitor with potent in vitro anti-HIV activity, an in vitro resistance profile different from those of other integrase inhibitors, and favorable preclinical safety and pharmacokinetics (PK). Randomized, double-blind, placebo-controlled single-dose and multiple-dose, dose escalation studies evaluated the PK, safety, and tolerability of S/GSK1349572 for healthy subjects. In the single-dose study, two cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 2, 5, 10, 25, 50, and 100 mg in an alternating panel design. In the multiple-dose study, three cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 10, 25, and 50 mg once daily for 10 days. A cytochrome P450 3A (CYP3A) substudy with midazolam was conducted with the 25-mg dose. Laboratory testing, vital signs, electrocardiograms (ECGs), and PK sampling were performed at regular intervals. S/GSK1349572 was well tolerated. Most adverse events (AEs) were mild, with a few moderate AEs reported. Headache was the most common AE. No clinically significant laboratory trends or ECG changes were noted. PK was linear over the dosage range studied. The steady-state geometric mean area under the concentration-time curve over a dosing interval (AUC(0-tau)) and maximum concentration of the drug in plasma (C-max) ranged from 16.7 mu g . h/ml (coefficient of variation [CV], 15%) and 1.5 mu g/ml (CV, 24%) at a 10-mg dose to 76.8 mu g . h/ml (CV, 19%) and 6.2 mu g/ml (CV, 15%) at a 50-mg dose, respectively. The geometric mean steady-state concentration at the end of the dosing interval (C-tau) with a 50-mg dose was 1.6 mu g/ml, approximately 25-fold higher than the protein-adjusted 90% inhibitory concentration (0.064 mu g/ml). The half-life was approximately 15 h. S/GSK1349572 had no impact on midazolam exposure, indicating that it does not modulate CYP3A activity. The PK profile suggests that once-daily, low milligram doses will achieve therapeutic concentrations.