Shelton Mark J, Wire Mary Beth, Lou Yu, Adamkiewicz Brigette, Min Sherene S
GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA.
Antimicrob Agents Chemother. 2006 Mar;50(3):928-34. doi: 10.1128/AAC.50.3.928-934.2006.
High-dose combinations of fosamprenavir (FPV) and ritonavir (RTV) were evaluated in healthy adult subjects in order to select doses for further study in multiple protease inhibitor (PI)-experienced patients infected with human immunodeficiency virus type 1. Two high-dose regimens, FPV 1,400 mg twice a day (BID) plus RTV 100 mg BID and FPV 1,400 mg BID plus RTV 200 mg BID, were planned to be compared to the approved regimen, FPV 700 mg BID plus RTV 100 mg BID, in a randomized three-period crossover study. Forty-two healthy adult subjects were enrolled, and 39 subjects completed period 1. Due to marked hepatic transaminase elevations, predominantly with FPV 1,400 mg BID plus RTV 200 mg BID, the study was terminated prematurely. For FPV 1,400 mg BID plus RTV 100 mg BID, the values for plasma amprenavir (APV) area under the concentration-time profile over the dosing interval (tau) at steady state [AUC(0-tau)], maximum concentration of drug in plasma (C(max)), and plasma concentration at the end of tau at steady state (C(tau)) were 54, 81, and 26% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) were 49% higher, 71% higher, and 11% lower, respectively, than those for FPV 700 mg BID plus RTV 100 mg BID. For FPV 1,400 mg BID plus RTV 200 mg BID, the values for plasma APV AUC(0-tau), C(max), and C(tau) were 26, 48, and 32% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) increased 4.15-fold, 4.17-fold, and 3.99-fold, respectively, compared to those for FPV 700 mg BID plus RTV 100 mg BID. FPV 1,400 mg BID plus RTV 200 mg BID is not recommended due to an increased rate of marked hepatic transaminase elevations and lack of pharmacokinetic advantage. FPV 1,400 mg BID plus RTV 100 mg BID is currently under clinical evaluation in multiple PI-experienced patients.
为了选择剂量以便在感染了1型人类免疫缺陷病毒的多种蛋白酶抑制剂（PI）经治患者中进行进一步研究，在健康成年受试者中对高剂量的福沙那韦（FPV）与利托那韦（RTV）联合用药进行了评估。计划在一项随机三周期交叉研究中，将两种高剂量方案，即FPV 1400 mg每日两次（BID）加RTV 100 mg BID和FPV 1400 mg BID加RTV 200 mg BID，与已批准的方案FPV 700 mg BID加RTV 100 mg BID进行比较。招募了42名健康成年受试者，39名受试者完成了第1阶段。由于显著的肝转氨酶升高，主要出现在FPV 1400 mg BID加RTV 200 mg BID组，该研究提前终止。对于FPV 1400 mg BID加RTV 100 mg BID，稳态给药间隔（tau）内血浆安普那韦（APV）浓度-时间曲线下面积[AUC(0-tau)]、血浆中药物的最大浓度（C(max)）以及tau结束时的稳态血浆浓度（C(tau)）的值分别比FPV 700 mg BID加RTV 100 mg BID高54%、81%和26%，而血浆RTV的AUC(0-tau)、C(max)和C(tau)的值分别比FPV 700 mg BID加RTV 100 mg BID高49%、71%和低11%。对于FPV 1400 mg BID加RTV 200 mg BID，血浆APV的AUC(0-tau)、C(max)和C(tau)的值分别比FPV 700 mg BID加RTV 100 mg BID高26%、48%和32%，与FPV 700 mg BID加RTV 100 mg BID相比，血浆RTV的AUC(0-tau)、C(max)和C(tau)的值分别增加了4.15倍、4.17倍和3.99倍。由于显著肝转氨酶升高的发生率增加且缺乏药代动力学优势，不推荐使用FPV 1400 mg BID加RTV 200 mg BID。FPV 1400 mg BID加RTV 100 mg BID目前正在多种PI经治患者中进行临床评估。
