Moyle G J, Youle M, Higgs C, Monaghan J, Prince W, Chapman S, Clendeninn N, Nelson M R
Chelsea and Westminster Hospital, London, England.
J Clin Pharmacol. 1998 Aug;38(8):736-43. doi: 10.1002/j.1552-4604.1998.tb04814.x.
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.
奈非那韦是一种强效且特异性的人类免疫缺陷病毒（HIV）蛋白酶抑制剂，在一项针对未接受过蛋白酶抑制剂治疗的HIV阳性男性的小型开放标签I/II期剂量范围研究中，对其安全性、抗逆转录病毒活性和药代动力学特征进行了评估。共有22例基线血浆HIV RNA≥20,000拷贝/mL且CD4+细胞计数在200至500个细胞/mm³之间的患者入组该研究。在这22例患者中，20例接受了活性评估；10例患者被分配至771毫克/天碱基当量（每日三次，每次300毫克）组，10例患者被分配至1,026毫克/天碱基当量（每日两次，每次600毫克）组，均接受单一疗法。使用的是奈非那韦胶囊制剂。初始研究期为28天；病毒载量降低1个对数10的患者有资格进入延长期并加用核苷类似物。未确定奈非那韦的最大耐受剂量。在28天的研究期间，771毫克组有4例（40%）患者、1,026毫克组有6例（60%）患者的血浆HIV RNA较基线水平降低至少1个对数。在这些患者中，5例患者在第28天之后血浆HIV RNA持续降低（2例接受771毫克/天，3例接受1,026毫克/天）。第28天时，771毫克组和1,026毫克组CD4+细胞计数较基线的中位数增加分别为216个细胞/mm³和86个细胞/mm³。口服给药后，第28天时，771毫克组奈非那韦血浆浓度在1小时达到最高值（2,966纳克/毫升），1,026毫克组在3小时达到最高值（3,157纳克/毫升）。22例患者的数据纳入了安全性分析；12例患者（55%）报告了至少1次2级或更严重（中度、重度或极重度）不良事件。最常见的2级或更严重不良事件是腹泻，接受771毫克/天的2例患者（20%）和接受1,026毫克/天的7例患者（70%）报告了腹泻；其次是恶心、胃肠胀气、乏力和头痛（771毫克组各有1例患者[10%]报告）以及头晕（接受1,026毫克/天的1例患者[10%]报告）。在继续服用奈非那韦较长时间（8至15个月）的小亚组（n = 6）中，大多数患者病毒学反应持续，耐受性良好。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。这项早期I/II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，并促使选择更高剂量用于II/III期试验，以进一步优化病毒学和免疫学反应。
