Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients
Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients
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DOI：
10.1097/00002030-199704000-00001
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发表时间：
1997-03-15
期刊：
影响因子：
3.8
通讯作者：
Back, DJ
中科院分区：
文献类型：
--
作者：
Merry, C;Barry, MG;Back, DJ
目的：参与蛋白酶抑制剂代谢的最重要的肝酶是细胞色素P450 3A 4（CYP 3A 4）。利托那韦（RIT）是一种强效的CYP 3A 4抑制剂，可抑制沙奎那韦（SQV）在健康志愿者中的代谢。在这项研究中，我们调查了SQV的动力学时，单独使用，并结合RIT在HIV infected patients.Design：SQV药代动力学测定7例晚期HIV疾病。稳态SQV的配置文件，获得了两个场合治疗后，SQV 600毫克，每日三次单独使用，当与RIT 300毫克，每日两次。方法：血液样品，获得了所有时间0，1，2，4，6和8小时后给药。离心后，将分离的血浆在58 ℃下加热至少30分钟以抑制HIV，并在-80 ℃下储存，直到使用高效液相色谱进行分析。结果：对于单独用SQV治疗的患者，SQV浓度-时间曲线下的面积（AUC（0.8h））有12倍的变异性，范围从293到3446 ng。h/ml。当与RIT联合使用时，SQV的最大血浆浓度显著增加[中位数（范围），146（57-702）vs 4795（1420-15810）ng/ml;与95%置信区间（CI）相似，2988-6819; P = 0.0006，Mann-Whitney U检验]。在存在RIT的情况下，SQV的AUC（0.8 h）也显著增加[中位数（范围），470（293-3446）vs 27 458（7357-108 001）ng。h/ml; 95%CI相似，16 628-35 111; P = 0.0006]。结论：对于某些患者，每日三次给予SQV 600 mg导致SQV血浆浓度非常低，可能几乎没有抗病毒作用。SQV与RIT的组合导致由酶抑制介导的显著药物相互作用，使患者暴露于非常高的SQV浓度和潜在毒性。如果考虑SQV加RIT的联合治疗，则应大大减少SQV的剂量。
Objective: The most important hepatic enzyme involved in the metabolism of protease inhibitors is cytochrome P450 3A4 (CYP3A4). Ritonavir (RIT) is a potent inhibitor of CYP3A4 and inhibits saquinavir (SQV) metabolism in healthy volunteers. In this study we investigated the kinetics of SQV when administered alone and in combination with RIT in HIV-infected patients.Design: SQV pharmacokinetics were determined in seven patients who had advanced HIV disease. Steady-state SQV profiles were obtained on two occasions following treatment with SQV 600 mg three times daily alone and when administered with RIT 300 mg twice daily.Methods: Blood samples were obtained al limes 0, 1, 2, 4, 6 and 8 h post-dosing. Following centrifugation, separated plasma was heated at 58 degrees C for at least 30 min to inactivate HIV and stored al -80 degrees C until analysis using high performance liquid chromatography.Results: For patients treated with SQV alone there was a 12-fold variability in the area under the SQV concentration-time curve (AUC(0.8h)) ranging from 293 to 3446 ng . h/ml. When combined with RIT there was a marked increase in the maximum plasma concentration of SQV [median (range), 146 (57-702) versus 4795 (1420-15810) ng/ml; similar to 95% confidence interval (CI), 2988-6819; P = 0.0006, Mann-Whitney U test]. The AUC(0.8h) for SQV was also significantly increased in the presence of RIT [median (range), 470 (293-3446) versus 27 458 (7357-108 001) ng . h/ml; similar to 95% CI, 16 628-35 111; P = 0.0006].Conclusions: For some patients, administration of SQV 600 mg three times daily results in very low SQV plasma levels and possibly little antiviral effect. Combination of SQV with RIT results in a significant drug interaction mediated by enzyme inhibition which exposes patients to very high SQV concentrations and potential toxicity. If combination therapy with SQV plus RIT is considered then the dose of SQV should be greatly reduced.