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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Safety, pharmacokinetics, and antiretroviral activity of the potent, specific human immunodeficiency virus protease inhibitor nelfinavir: results of a phase I/II trial and extended follow-up in patients infected with human immunodeficiency virus.
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Safety, pharmacokinetics, and antiretroviral activity of the potent, specific human immunodeficiency virus protease inhibitor nelfinavir: results of a phase I/II trial and extended follow-up in patients infected with human immunodeficiency virus.

机译：有效的，特定的人类免疫缺陷病毒蛋白酶抑制剂奈芬那韦的安全性，药代动力学和抗逆转录病毒活性：I / II期试验的结果以及对感染人类免疫缺陷病毒的患者进行后续随访的结果。

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摘要

The safety, antiretroviral activity, and pharmacokinetic profile of nelfinavir, a potent and specific inhibitor of human immunodeficiency virus (HIV) protease, were assessed in a small open-label phase I/II dose-ranging study in protease inhibitor-naive HIV-positive men. A total of 22 patients with baseline plasma HIV RNA > or = 20,000 copies/mL and CD4+ counts between 200 and 500 cells/mm3 were enrolled in the study. Of the 22 patients, 20 were evaluated for activity; 10 patients assigned to 771 mg/day base equivalent (300 mg three times daily) and 10 patients assigned to 1,026 mg/day base equivalent (600 mg twice daily) given monotherapy. A capsule formulation of nelfinavir was used. The initial study period was 28 days; patients showing a virologic response of 1 log10 reduction were eligible for enrollment in an extension phase and addition of nucleoside analogues. A maximally tolerated dose of nelfinavir was not established. A dose-response relationship was observed for four (40%) patients in the 771-mg group and six (60%) patients in the 1,026-mg group experiencing a reduction from baseline in plasma HIV RNA of at lest 1 log during the 28-day study. Of these patients, five sustained the reduction in plasma HIV RNA beyond day 28 (2 patients receiving 771 mg/day and 3 patients receiving 1,026 mg/day). Median increases from baseline in CD4+ counts at day 28 were 216 cell/mm3 and 86 cell/mm3 in the 771-mg and 1,026-mg groups, respectively. After oral administration, median nelfinavir plasma concentrations on day 28 reached a maximum at 1 hour (2,966 ng/mL) in the 771-mg group and at 3 hours (3,157 ng/mL) in the 1,026-mg group. Data for 22 patients were included in the safety analysis; 12 patients (55%) reported at least one grade 2 or worse (moderate, severe, or very severe) adverse event. The most common grade 2 or worse adverse event was diarrhea, reported by two patients (20%) receiving 771 mg/day and seven patients (70%) receiving 1,026 mg/day; followed by nausea, flatulence, asthenia, and headache (each reported in 1 patient [10%] in the 771-mg group) and dizziness (reported in 1 patient [10%] receiving 1,026 mg/day). In the small subgroup (n = 6) who continued taking nelfinavir for longer periods (between 8 and 15 months), virologic responses were sustained in the majority of patients with good tolerability. Nelfinavir is an active HIV-protease inhibitor with favorable pharmacokinetics, good tolerability, and sustained antiviral effects. Results of this early phase I/II dose-ranging study provided data for the safety and antiretroviral activity of nelfinavir and led to the selection of higher doses for phase II/III trials to further optimize virologic and immunologic responses.
机译：奈芬那韦是一种有效且特异性的人类免疫缺陷病毒（HIV）蛋白酶抑制剂，其安全性，抗逆转录病毒活性和药代动力学特征已在未经蛋白酶抑制剂治疗的未感染HIV阳性的小型开放标签I / II期剂量范围研究中进行了评估男人们该研究共纳入22名基线血浆HIV RNA>或= 20,000拷贝/ mL，且CD4 +计数在200至500个细胞/ mm3之间的患者。在22名患者中，有20名接受了活动评估。 10名患者接受单药治疗，每日基本剂量为771 mg /天（每天3次，每次300 mg），10名患者接受单药治疗，每日基本剂量为1,026 mg /天（600毫克，每天两次）。使用了奈非那韦的胶囊制剂。初始研究期为28天;病毒学应答降低1 log10的患者有资格参加扩展期并加入核苷类似物。未确定最大耐受剂量的奈非那韦。在28 mg剂量期间，在771 mg组中有四（40％）位患者和1,026 mg组中有六位（60％）患者出现了剂量-反应关系，血浆HIV RNA至少比基线降低了1 log天学习。在这些患者中，有五名患者在第28天后血浆HIV RNA持续下降（2名患者接受771 mg /天和3名患者接受1,026 mg /天）。在第28天，771 mg和1,026 mg组的CD4 +计数从基线的中位数增加分别为216细胞/ mm3和86细胞/ mm3。口服后，771 mg组在第28天的奈非那韦血浆中值浓度在第1小时达到最大值（2,966 ng / mL），而1,026 mg组在第3天达到中值最高浓度（3,157 ng / mL）。安全性分析包括22例患者的数据。 12名患者（55％）报告了至少一种2级或更严重（中度，严重或非常严重）不良事件。最常见的2级或更严重的不良事件是腹泻，其中2名患者（20％）每天接受771 mg的剂量，7名患者（70％）每天接受1,026 mg的剂量;其次是恶心，肠胃气胀，虚弱和头痛（在771 mg组中每例报告1例患者[10％]）和头晕（在1例患者[10％]中报告每天1,026 mg服用）。在较小的亚组（n = 6）中，他们继续服用奈非那韦更长的时间（8到15个月），大多数耐受性良好的患者持续接受病毒学应答。奈非那韦是一种活性HIV蛋白酶抑制剂，具有良好的药代动力学，良好的耐受性和持续的抗病毒作用。 I / II期早期剂量范围研究的结果为奈非那韦的安全性和抗逆转录病毒活性提供了数据，并为II / III期试验选择了更高剂量，以进一步优化病毒学和免疫学应答。

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