Boffito Marta, Miralles Diego, Hill Andrew
Chelsea and Westminster Hospital, London, United Kingdom.
HIV Clin Trials. 2008 Nov-Dec;9(6):418-27. doi: 10.1310/hct0906-418.
Darunavir is a new protease inhibitor (PI) with in vitro activity against wild-type and PI-resistant HIV; it is used with the pharmacokinetic booster ritonavir. The currently approved dose of darunavir/ritonavir is 600/100 mg twice-daily, licensed for treatment-experienced patients. However, during the clinical development of darunavir, a range of once-daily and twice-daily doses of darunavir/ritonavir were evaluated. The relatively long terminal elimination plasma half-life of darunavir (15 hours) supports once-daily dosing. In treatment-naïve patients, the ARTEMIS trial has shown high rates of HIV RNA suppression for darunavir-ritonavir at the 800/100 mg once-daily dose (84% with HIV RNA <50 copies/mL at Week 48) versus a control arm of lopinavir/ritonavir (78% with HIV RNA <50 copies/mL). In a population pharmacokinetic substudy, darunavir 24-hour minimum plasma concentration levels remained above the predefined EC(50) of 55 ng/mL for all 335 patients evaluated in the ARTEMIS trial. Once-daily darunavir/ritonavir has also been evaluated in treatment-experienced patients in the TMC114-C207 proof-of-principle trial and the POWER 1 and 2 trials. For the overall POWER trial population, with significant baseline resistance to PIs, the rates of HIV RNA suppression <50 copies/mL at Week 24 for darunavir/ritonavir 800/100 mg once-daily [DOSAGE ERROR CORRECTED] were lower than for the 600/100 mg twice-daily dosage (31% vs. 47%, respectively). However, for patients with no genotypic darunavir resistance-associated mutations at baseline, rates of HIV RNA suppression were 62% and 67% for the 800/100 mg once-daily and 600/100 mg twice-daily doses. The current evidence from clinical trials of darunavir/ritonavir supports the efficacy of the 800/100 mg once-daily dose for treatment-naïve patients and further evaluation for treatment-experienced patients with no genotypic resistance to darunavir.
地瑞那韦是一种新型蛋白酶抑制剂（PI），对野生型和对PI耐药的HIV具有体外活性；它与药代动力学增强剂利托那韦联合使用。目前批准的地瑞那韦/利托那韦剂量为600/100毫克，每日两次，适用于有治疗经验的患者。然而，在地瑞那韦的临床开发过程中，评估了一系列地瑞那韦/利托那韦的每日一次和每日两次剂量。地瑞那韦相对较长的终末消除血浆半衰期（15小时）支持每日一次给药。在初治患者中，ARTEMIS试验显示，地瑞那韦-利托那韦每日一次剂量800/100毫克时，HIV RNA抑制率较高（第48周时84%的患者HIV RNA<50拷贝/毫升），而洛匹那韦/利托那韦对照组为78%（HIV RNA<50拷贝/毫升）。在一项群体药代动力学亚研究中，在ARTEMIS试验中评估的所有335例患者中，地瑞那韦24小时最低血浆浓度水平均保持在预定义的55纳克/毫升的EC(50)以上。每日一次的地瑞那韦/利托那韦也在TMC114-C207原理验证试验以及POWER 1和2试验中有治疗经验的患者中进行了评估。对于整个POWER试验人群，对PI有显著的基线耐药性，地瑞那韦/利托那韦每日一次800/100毫克[剂量错误已纠正]在第24周时HIV RNA抑制率<50拷贝/毫升低于每日两次600/100毫克剂量（分别为31%对47%）。然而，对于基线时没有与地瑞那韦耐药相关的基因型突变的患者，每日一次800/100毫克和每日两次600/100毫克剂量的HIV RNA抑制率分别为62%和67%。目前来自地瑞那韦/利托那韦临床试验的证据支持每日一次800/100毫克剂量对初治患者的疗效，并支持对没有对地瑞那韦基因型耐药性的有治疗经验的患者进行进一步评估。
