Sadler Brian M, Stein Daniel S
GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709, USA.
Ann Pharmacother. 2002 Jan;36(1):102-18. doi: 10.1345/aph.10423.
To review the pharmacokinetics, pharmacodynamics, drug interactions, and dosage and administration information of amprenavir.
An extensive review of the literature (MEDLINE search from 1994 to April 2001) relating to the clinical pharmacology of the HIV protease inhibitors was conducted. Meeting abstracts or full presentations and data submitted to the Food and Drug Administration were also reviewed.
The data on pharmacokinetics, pharmacodynamics, drug interactions, and drug resistance were obtained from in vitro studies and open-label and controlled clinical trials.
Like all HIV protease inhibitors, amprenavir interrupts the maturation phase of the HIV replicative cycle by forming an inhibitor-enzyme complex, which prevents HIV protease from binding with its normal substrates (biologically inactive viral polyproteins). Amprenavir has an enzyme inhibition constant (Ki = 0.6 nM) that falls within the Ki range of the other protease inhibitors. Amprenavir's in vitro 50% inhibitory concentration (IC50) against wild-type clinical HIV isolates is 14.6 +/- 12.5 ng/mL (mean +/- SD). Pharmacodynamic modeling indicates that, as is the case with other protease inhibitors, the concentration-response curve for amprenavir plateaus at amprenavir trough values above the IC50 for these isolates. This exposure-activity relationship, plus such favorable pharmacokinetic parameters as a long terminal elimination half-life (7-10 h), makes amprenavir an attractive drug of choice when considering potent antiretrovirals. The higher trough exposure obtained with amprenavir coadministered with ritonavir may allow effective treatment of patients with decreased susceptibility viral isolates and once-daily dosing. Amprenavir has been approved for adults and children; the recommended capsule doses are 1200 mg twice daily for adults and 20 mg/kg twice daily or 15 mg/kg 3 times daily for children < 13 years of age or adolescents < 50 kg. The recommended dose for amprenavir oral solution is 1.5 mL/kg twice daily or 1.1 mL/kg 3 times daily.
The clinical pharmacology, exposure-activity relationship, and drug resistance profile of amprenavir support the use of this potent HIV protease inhibitor in combination antiretroviral regimens, especially for persons who have experienced virologic failure while on protease inhibitor-containing regimens.
综述安普那韦的药代动力学、药效学、药物相互作用以及剂量和用法信息。
对1994年至2001年4月期间与HIV蛋白酶抑制剂临床药理学相关的文献进行了广泛综述（MEDLINE检索）。还查阅了会议摘要或完整报告以及提交给美国食品药品监督管理局的数据。
药代动力学、药效学、药物相互作用和耐药性的数据来自体外研究以及开放标签和对照临床试验。
与所有HIV蛋白酶抑制剂一样，安普那韦通过形成抑制剂 - 酶复合物来中断HIV复制周期的成熟阶段，这会阻止HIV蛋白酶与其正常底物（无生物活性的病毒多聚蛋白）结合。安普那韦的酶抑制常数（Ki = 0.6 nM）处于其他蛋白酶抑制剂Ki范围之内。安普那韦对野生型临床HIV分离株的体外50%抑制浓度（IC50）为14.6 +/- 12.5 ng/mL（平均值 +/- 标准差）。药效学模型表明，与其他蛋白酶抑制剂情况相同，当安普那韦谷值高于这些分离株的IC50时，其浓度 - 反应曲线趋于平稳。这种暴露 - 活性关系，加上诸如长的终末消除半衰期（7 - 10小时）等有利的药代动力学参数，使得在考虑强效抗逆转录病毒药物时，安普那韦成为一种有吸引力的选择药物。与利托那韦联合使用时，安普那韦获得的更高谷值暴露量可能允许有效治疗对病毒分离株敏感性降低的患者，并实现每日一次给药。安普那韦已被批准用于成人和儿童；推荐的胶囊剂量为成人每日两次，每次1200 mg，13岁以下儿童或体重<50 kg的青少年每日两次，每次20 mg/kg或每日三次，每次15 mg/kg。安普那韦口服溶液的推荐剂量为每日两次，每次1.5 mL/kg或每日三次，每次1.1 mL/kg。
安普那韦的临床药理学、暴露 - 活性关系和耐药性特征支持在联合抗逆转录病毒治疗方案中使用这种强效HIV蛋白酶抑制剂，特别是对于在含蛋白酶抑制剂方案治疗期间出现病毒学失败的患者。
