HIGH-DOSE NEVIRAPINE - SAFETY, PHARMACOKINETICS, AND ANTIVIRAL EFFECT IN PATIENTS WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION
HIGH-DOSE NEVIRAPINE - SAFETY, PHARMACOKINETICS, AND ANTIVIRAL EFFECT IN PATIENTS WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION
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DOI：
10.1093/infdis/171.3.537
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发表时间：
1995-03-01
影响因子：
6.4
通讯作者：
RICHMAN, DD
中科院分区：
文献类型：
--
作者：
HAVLIR, D;CHEESEMAN, SH;RICHMAN, DD
奈韦拉平是一种有效的非核苷类逆转录酶抑制剂，由于选择了耐药病毒，因此在小于或等于 200 mg/天的剂量下即可产生短暂的抗病毒作用。为了检验更高水平的奈韦拉平是否可以产生持续的抗病毒活性，在 21 名患者中研究了 400 毫克/天的奈韦拉平的安全性、药代动力学和抗病毒活性。所有患者的免疫复合物解离的 p24 抗原和血清人类免疫缺陷病毒 RNA 浓度均迅速下降，10 名患者中有 8 名在 8 周时下降超过 50%。在第 12 周时，从所有测试对象中分离出奈韦拉平耐药病毒：平均血浆谷水平（4.0 μg/mL [15.8 μM]）超过了耐药病毒的平均 IC50。 48% 的患者出现皮疹，并且是 6 例患者的剂量限制性毒性因素。这些数据表明，对选择耐药病毒的强效抗病毒化合物进行临床测试是合理的，以确定是否可以达到足以克服耐药病毒的药物血清水平。
Nevirapine, a potent nonnucleoside reverse transcriptase inhibitor, produces a transient antiviral effect at less than or equal to 200 mg/day due to the selection of resistant virus. To examine if higher levels of nevirapine could produce sustained antiviral activity, its safety, pharmacokinetics, and antiviral activity at 400 mg/day were studied in 21 patients. There was a rapid reduction in immune complex-dissociated p24 antigen and serum human immunodeficiency virus RNA concentration in all patients, and 8 of 10 patients had >50% reduction at 8 weeks. Nevirapine-resistant virus was isolated from all subjects tested at 12 weeks: The mean plasma trough level (4.0 mu g/mL [15.8 mu M]) exceeded the mean IC50 of resistant virus. Rash developed in 48% of patients and was a dose-limiting toxicity factor in 6. These data suggest that clinical testing of potent antiviral compounds that select for drug-resistant virus is justified to determine if serum levels of drug sufficient to overcome resistant virus can be attained.