Vella S, Floridia M
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Clin Pharmacokinet. 1998 Mar;34(3):189-201. doi: 10.2165/00003088-199834030-00002.
Saquinavir is an HIV protease inhibitor with no, or limited, effect on the activity of other structurally related human aspartic proteinases. As with other HIV protease inhibitors, saquinavir inhibits the cleavage of the gag-pol protein substrate leading to the release of structurally defective and functionally inactive viral particles. It is active on both HIV-1 and HIV-2, and also has activity on chronically infected cells and HIV strains resistant to reverse transcriptase inhibitors. Synergy of action has been observed with other antiretroviral drugs. Saquinavir is characterised by a low bioavailability which is further reduced in the fasting state. Metabolism is mainly hepatic through cytochrome P450 (CYP) 3A4, but intestinal metabolism through the same system has also been reported. To achieve higher drug plasma concentrations and increase the antiviral effect, a new formulation of saquinavir with a higher bioavailability has recently been introduced. Higher plasma drug concentrations may also be obtained by combining the drug with CYP blockers, such as ritonavir or ketoconazole. Because of its metabolic interference with the CYP system, saquinavir cannot be coadministered with astemizole, terfenadine or cisapride. Rifampicin (rifampin) is also contraindicated because coadministration can lead to decreases in saquinavir concentrations. Interactions have also been reported with other drugs metabolised through the same system, including non-nucleoside reverse transcriptase inhibitors and HIV protease inhibitors. Resistance has been observed after both in vitro and in vivo drug exposure, with a relatively specific mutation profile compared with other protease inhibitors. Saquinavir is generally well tolerated, with mild gastrointestinal symptoms representing the most commonly observed adverse effects. Although characterized by low bioavailability, in phase III trials saquinavir has been shown to have clinical efficacy in terms of survival and progression rate. As with the other protease inhibitors, saquinavir should be used in combination with other antiretroviral drugs. Current therapeutic guidelines, however, recommend the selection of an initial treatment regimen with other protease inhibitors with higher in vivo activity in terms of RNA and CD4 response. The results of ongoing studies will clarify to what extent a new saquinavir formulation, recently introduced, is superior to the previous one in terms of antiviral activity and to provide comparisons with other protease inhibitors. Further studies are also needed to define the best place of saquinavir within treatment strategies based on protease inhibitors, particularly in respect to the optimal sequence for its use with other protease inhibitors, and the dynamics of cross-resistance and its role within regimens based on the combination of protease inhibitors.
沙奎那韦是一种HIV蛋白酶抑制剂，对其他结构相关的人天冬氨酸蛋白酶的活性没有或只有有限的影响。与其他HIV蛋白酶抑制剂一样，沙奎那韦抑制gag-pol蛋白底物的裂解，导致释放出结构有缺陷且功能无活性的病毒颗粒。它对HIV-1和HIV-2均有活性，对慢性感染细胞和对逆转录酶抑制剂耐药的HIV毒株也有活性。已观察到与其他抗逆转录病毒药物的协同作用。沙奎那韦的特点是生物利用度低，在禁食状态下会进一步降低。代谢主要通过细胞色素P450（CYP）3A4在肝脏进行，但也有报道称通过同一系统在肠道进行代谢。为了达到更高的药物血浆浓度并增强抗病毒效果，最近引入了一种生物利用度更高的沙奎那韦新制剂。将该药物与CYP阻滞剂（如利托那韦或酮康唑）联合使用也可获得更高的血浆药物浓度。由于其对CYP系统的代谢干扰，沙奎那韦不能与阿司咪唑、特非那定或西沙必利合用。利福平也属禁忌，因为合用会导致沙奎那韦浓度降低。还报道了与通过同一系统代谢的其他药物的相互作用，包括非核苷逆转录酶抑制剂和HIV蛋白酶抑制剂。在体外和体内药物暴露后均观察到耐药性，与其他蛋白酶抑制剂相比，其突变谱相对特异。沙奎那韦一般耐受性良好，最常见的不良反应是轻度胃肠道症状。尽管沙奎那韦的特点是生物利用度低，但在III期试验中已证明其在生存和进展率方面具有临床疗效。与其他蛋白酶抑制剂一样，沙奎那韦应与其他抗逆转录病毒药物联合使用。然而，当前的治疗指南建议选择初始治疗方案时使用其他在RNA和CD4反应方面具有更高体内活性的蛋白酶抑制剂。正在进行的研究结果将阐明最近引入的沙奎那韦新制剂在抗病毒活性方面优于前一种制剂的程度，并与其他蛋白酶抑制剂进行比较。还需要进一步研究来确定沙奎那韦在基于蛋白酶抑制剂的治疗策略中的最佳位置，特别是关于其与其他蛋白酶抑制剂联合使用的最佳顺序，以及交叉耐药的动态变化及其在基于蛋白酶抑制剂联合使用的治疗方案中的作用。
