Ruane Peter J, Luber Andrew D, Wire Mary Beth, Lou Yu, Shelton Mark J, Lancaster C Tracey, Pappa Keith A
Light Source Medical, Los Angeles, CA, USA.
Antimicrob Agents Chemother. 2007 Feb;51(2):560-5. doi: 10.1128/AAC.00560-06. Epub 2006 Nov 6.
Once-daily (QD) fosamprenavir (FPV) at 1,400 mg boosted with low-dose ritonavir (RTV) at 200 mg is effective when it is used in combination regimens for the initial treatment of human immunodeficiency virus infection. Whether a lower RTV boosting dose (i.e., 100 mg QD) could ensure sufficient amprenavir (APV) concentrations with improved safety/tolerability is unknown. This randomized, two 14-day-period, crossover pharmacokinetic study compared the steady-state plasma APV concentrations, safety, and tolerability of FPV at 1,400 mg QD boosted with either 100 mg or 200 mg of RTV QD in 36 healthy volunteers. Geometric least-square (GLS) mean ratios and the associated 90% confidence intervals (CIs) were estimated for plasma APV maximum plasma concentrations (Cmax), the area under the plasma concentration-time curve over the dosing period (AUC0-tau), and trough concentrations (Ctau) during each dosing period. Equivalence between regimens (90% CIs of GLS mean ratios, 0.80 to 1.25) was observed for the plasma APV AUC0-tau (GLS mean ratio, 0.90 [90% CI, 0.84 to 0.96]) and Cmax (0.97 [90% CI, 0.91 to 1.04]). The APV Ctau was 38% lower with RTV at 100 mg QD than with RTV at 200 mg QD (GLS mean ratio, 0.62 [90% CI, 0.55 to 0.69]) but remained sixfold higher than the protein-corrected 50% inhibitory concentration for wild-type virus, with the lowest APV Ctau observed during the 100-mg QD period being nearly threefold higher. The GLS mean APV Ctau was 2.5 times higher than the historical Ctau for unboosted FPV at 1,400 mg twice daily. Fewer clinical adverse drug events and smaller increases in triglyceride levels were observed with the RTV 100-mg QD regimen. Clinical trials evaluating the efficacy and safety of FPV at 1,400 mg QD boosted by RTV at 100 mg QD are now under way with antiretroviral therapy-naïve patients.
每日一次（QD）服用1400毫克福沙普那韦（FPV）并用200毫克低剂量利托那韦（RTV）增强，用于人类免疫缺陷病毒感染初始治疗的联合方案时是有效的。较低的RTV增强剂量（即每日一次100毫克）能否确保足够的安普那韦（APV）浓度并提高安全性/耐受性尚不清楚。这项随机、两个14天周期的交叉药代动力学研究比较了36名健康志愿者中每日一次服用1400毫克FPV并用每日一次100毫克或200毫克RTV增强后的稳态血浆APV浓度、安全性和耐受性。对每个给药期血浆APV的最大血浆浓度（Cmax）、给药期内血浆浓度-时间曲线下面积（AUC0-tau）和谷浓度（Ctau）估计几何最小二乘（GLS）平均比值及相关的90%置信区间（CI）。在血浆APV的AUC0-tau（GLS平均比值，0.90[90%CI，0.84至0.96]）和Cmax（0.97[90%CI，0.91至1.04]）方面观察到各方案之间的等效性（GLS平均比值的90%CI，0.80至1.25）。每日一次100毫克RTV时的APV Ctau比每日一次200毫克RTV时低38%（GLS平均比值，0.62[90%CI，0.55至0.69]），但仍比野生型病毒的蛋白校正50%抑制浓度高6倍，在每日一次100毫克期间观察到的最低APV Ctau几乎高3倍。GLS平均APV Ctau比每日两次服用1400毫克未增强FPV时的历史Ctau高2.5倍。每日一次100毫克RTV方案观察到的临床不良药物事件较少，甘油三酯水平升高幅度较小。目前正在对抗逆转录病毒治疗初治患者进行评估每日一次1400毫克FPV并用每日一次100毫克RTV增强后的疗效和安全性的临床试验。
