Wood Robin, Arasteh Keikawus, Stellbrink Hans-Jürgen, Teofilo Eugenio, Raffi François, Pollard Richard B, Eron Joseph, Yeo Jane, Millard Judith, Wire Mary Beth, Naderer Odin J
Somerset Hospital, University of Cape Town, Cape Town, South Africa.
Antimicrob Agents Chemother. 2004 Jan;48(1):116-23. doi: 10.1128/AAC.48.1.116-123.2004.
This study compared the plasma amprenavir pharmacokinetics of the human immunodeficiency virus (HIV) protease inhibitors amprenavir (Agenerase) 1,200 mg twice daily (BID) and the amprenavir prodrug GW433908, a formulation that substantially reduces the number of tablets per dose compared with amprenavir, at doses of 1,395 mg and 1,860 mg BID, in combination with abacavir 300 mg BID and lamivudine 150 mg BID in patients with HIV infection. Overall, 78 patients received study treatment. Compared with amprenavir 1,200 mg BID, both GW433908 1,395 mg BID and GW433908 1,860 mg BID delivered equivalent steady-state (ss) values for area under the plasma amprenavir concentration-time curve (AUC) at the end of a dosing interval (tau), lower maximum plasma amprenavir concentrations (30% lower), and higher plasma amprenavir concentrations at the end of a dosing interval (28% higher for GW433908 1,395 mg BID and 46% higher for GW433908 1,860 mg BID). Time-variant plasma amprenavir pharmacokinetics were observed with reductions in plasma amprenavir exposure over the first 4 weeks of dosing; the decrease in plasma amprenavir AUC(tau,ss) versus the AUC from 0 h to infinity was 27% for GW43308 1,395 mg, 45% for GW433908 1,860 mg, and 23% for amprenavir 1,200 mg. All three regimens reduced plasma HIV-1 RNA ( approximately 2 log(10) copies/ml) and increased CD4(+) cell counts ( approximately 100 cells/mm(3)) over the initial 28 days. Adverse event profiles were consistent with those previously reported for amprenavir. Although not statistically tested, the GW433908 groups appeared to have fewer gastrointestinal symptoms. In conclusion, the protease inhibitor GW433908 delivered comparable plasma amprenavir concentrations to those delivered by amprenavir 1,200 mg BID. GW433908, in combination with abacavir and lamivudine, demonstrated potent antiviral activity and was generally well tolerated over a 4-week period.
本研究比较了人类免疫缺陷病毒（HIV）蛋白酶抑制剂安普那韦（Agenerase）每日两次、每次1200毫克（bid）与安普那韦前体药物GW433908的血浆安普那韦药代动力学。与安普那韦相比，GW433908剂型大幅减少了每剂量的片剂数量。在HIV感染患者中，将GW433908以每日两次、每次1395毫克和1860毫克的剂量与阿巴卡韦每日两次、每次300毫克及拉米夫定每日两次、每次150毫克联合使用。总体而言，78名患者接受了研究治疗。与每日两次服用1200毫克安普那韦相比，每日两次服用1395毫克GW433908和每日两次服用1860毫克GW433908在给药间隔（tau）结束时的血浆安普那韦浓度-时间曲线下面积（AUC）的稳态（ss）值相当，最大血浆安普那韦浓度较低（低30%），且在给药间隔结束时血浆安普那韦浓度较高（每日两次服用1395毫克GW433908高28%，每日两次服用1860毫克GW433908高46%）。观察到随时间变化的血浆安普那韦药代动力学，在给药的前4周血浆安普那韦暴露量降低；与0小时至无穷大的AUC相比，每日两次服用1395毫克GW43308的血浆安普那韦AUC（tau，ss）降低27%，每日两次服用1860毫克GW433908降低45%，每日两次服用1200毫克安普那韦降低23%。在最初的28天内，所有三种治疗方案均降低了血浆HIV-1 RNA（约2 log₁₀拷贝/毫升）并增加了CD4⁺细胞计数（约100个细胞/立方毫米）。不良事件谱与先前报道的安普那韦一致。虽然未进行统计学检验，但GW433908组的胃肠道症状似乎较少。总之，蛋白酶抑制剂GW433908产生的血浆安普那韦浓度与每日两次服用1200毫克安普那韦相当。GW433908与阿巴卡韦和拉米夫定联合使用时，在4周期间显示出强效抗病毒活性且总体耐受性良好。
