Goujard Cecile, Vincent Isabelle, Meynard Jean-Luc, Choudet Nathalie, Bollens Diane, Rousseau Cyril, Demarles Didier, Gillotin Catherine, Bidault Roselyne, Taburet Anne-Marie
Internal Medicine Department, Bicetre Hospital, Le Kremlin Bicetre, France.
Antimicrob Agents Chemother. 2003 Jan;47(1):118-23. doi: 10.1128/AAC.47.1.118-123.2003.
The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C(min,ss)) was 1.92 microg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 microg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C(max,ss)) was 7.12 microg/ml, the area under the concentration-time curve from 0 to 10 h (AUC(0-10)) was 32.06 microg. h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUC(ss)) was 35.74 microg. h/ml. Decreases in the mean values of C(min,ss) (29%), C(max,ss) (42%), AUC(0-10) (42%), and AUC(ss) (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C(min,ss) markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C(min,ss) above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.
蛋白酶抑制剂（PI）利托那韦用作细胞色素P450 3A4的强效抑制剂，可增强同时服用的PI的活性，从而提高血浆PI水平，简化给药方案，并增强对耐药病毒的疗效。本项开放标签、多剂量研究的目的是确定在接受不同抗逆转录病毒联合治疗（包括或不包括非核苷类逆转录酶抑制剂[NNRTI]）的1型人类免疫缺陷病毒（HIV-1）感染成人中，每日两次服用600 mg安普那韦和每日两次服用100 mg利托那韦的稳态药代动力学。19名患者完成了该研究。对于未接受NNRTI的同时服用安普那韦和利托那韦的患者，稳态平均最低血浆安普那韦浓度（C(min,ss)）为1.92μg/ml，而对于同时服用安普那韦、利托那韦和依非韦伦的患者，该浓度为1.36μg/ml。对于未接受NNRTI的同时服用安普那韦-利托那韦的患者，稳态平均血浆安普那韦峰浓度（C(max,ss)）为7.12μg/ml，0至10小时浓度-时间曲线下面积（AUC(0-10)）为32.06μg·h/ml，稳态下给药间隔（12小时）的浓度-时间曲线下面积（AUC(ss)）为35.74μg·h/ml。当依非韦伦与安普那韦-利托那韦同时给药时，安普那韦的C(min,ss)、C(max,ss)、AUC(0-10)和AUC(ss)的平均值分别下降了29%、42%、42%和40%。未观察到意外的副作用。正如预期的那样，安普那韦与利托那韦同时给药导致安普那韦的C(min,ss)明显高于先前报道的市售剂量安普那韦的C(min,ss)。当安普那韦-利托那韦与依非韦伦同时给药时，安普那韦-利托那韦的平均安普那韦C(min,ss)维持在先前针对野生型HIV-1分离株和从接受过PI治疗的患者中分离出的HIV-1毒株所确定的安普那韦平均50%抑制浓度之上。这些数据支持使用低剂量利托那韦来提高安普那韦的暴露水平并增强安普那韦的疗效。
