Pharmacokinetics and Bioavailability of an Integrase and Novel Pharmacoenhancer-Containing Single-Tablet Fixed-Dose Combination Regimen for the Treatment of HIV
Pharmacokinetics and Bioavailability of an Integrase and Novel Pharmacoenhancer-Containing Single-Tablet Fixed-Dose Combination Regimen for the Treatment of HIV
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DOI：
10.1097/qai.0b013e3181eb376b
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发表时间：
2010-11-01
影响因子：
3.6
通讯作者：
Kearney, Brian P.
中科院分区：
文献类型：
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作者：
German, Polina;Warren, David;Kearney, Brian P.
目的：评价依维替格雷(EVG)、恩曲他滨(FTC)、富马酸替诺福韦(TDF)和药物增强剂考比司特(GS-9350，Cobi)作为固定剂量复合片(FDC)的相对生物利用度和药代动力学。所有的治疗都是在早上进行为期10天的饮食治疗，间隔2天。结果：44名受试者入选，42名受试者完成所有疗程。所有研究治疗总体耐受性良好。与利托那韦增强的EVG相比，EVG/COBI 150 mg/FTC/TDF的血药浓度-时间曲线下EVG面积的几何最小二乘均值比(GMR)[90%可信区间(CI)]分别为118(110~126)、108(100~116)和110(95.3~127)。相对于FTC+TDF，FTC GMR和90%CI分别为AUC(Tau)127(115~140)、C(Max)121(107~137)和C(Tau)126(118~136)；替诺福韦(TFV)对AUC(Tau)、C(Max)和C(Tau)的GMR和90%CI分别为118(114~122)、130(122~138)和124(119~129)，EVG/Cobi 150 mg/FTC/TDF。结论：与目前批准的单独用药相比，含Cobi150 mg的固定剂量复合片可产生较高的EVG C(Tau)浓度和临床等效的替诺福韦和FTC暴露，因此被选为后续评估的对象。
Objective: This study evaluated the relative bioavailability and pharmacokinetics of elvitegravir (EVG), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and a investigational pharmacoenhancer, cobicistat (GS-9350, COBI) coformulated as a fixed-dose combination tablet (FDC) compared with ritonavir-boosted EVG and FTC + TDF in healthy subjects.Methods: Subjects were randomized to 1 of 2 sequences. All treatments were administered in the morning for 10 days with food, separated by a 2-day washout. Blood samples were collected over 24 hours with the last dose of each treatment.Results: Forty-four subjects enrolled, 42 subjects completed all periods. All study treatments were generally well tolerated. Relative to ritonavir-boosted EVG, the geometric least-squares means ratios (GMR) [90% confidence interval (CI)] for EVG area under plasma concentration-time curve from time zero until the end of the dosing interval (AUC)(tau), maximum concentration (C(max)), and trough concentration (C(tau)) were 118 (110 to 126), 108 (100 to 116), and 110 (95.3 to 127), respectively, with EVG/COBI 150 mg/FTC/TDF. Relative to FTC + TDF, FTC GMR, and 90% CI were 127 (115 to 140) for AUC(tau), 121 (107 to 137) for C(max), and 126 (118 to 136) for C(tau); tenofovir (TFV) GMR and 90% CI were 118 (114 to 122), 130 (122 to 138), and 124 (119 to 129) for AUC(tau), C(max), and C(tau), respectively, with EVG/COBI 150 mg/FTC/TDF.Conclusions: Fixed-dose combination tablet containing COBI 150 mg resulted in desired high EVG C(tau) concentrations and clinically equivalent tenofovir and FTC exposures relative to currently approved individual agents and was thus selected for subsequent evaluation.