Havlir D, Cheeseman S H, McLaughlin M, Murphy R, Erice A, Spector S A, Greenough T C, Sullivan J L, Hall D, Myers M
Department of Medicine, University of California, San Diego.
J Infect Dis. 1995 Mar;171(3):537-45. doi: 10.1093/infdis/171.3.537.
Nevirapine, a potent nonnucleoside reverse transcriptase inhibitor, produces a transient antiviral effect at < or = 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 micrograms/mL [15.8 microM]) 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.
奈韦拉平是一种强效非核苷类逆转录酶抑制剂，由于耐药病毒的产生，在每日剂量小于或等于200毫克时会产生短暂的抗病毒作用。为了研究更高剂量的奈韦拉平是否能产生持续的抗病毒活性，对21例患者进行了每日400毫克剂量时的安全性、药代动力学及抗病毒活性研究。所有患者的免疫复合物解离p24抗原及血清人类免疫缺陷病毒RNA浓度均迅速下降，10例患者中有8例在8周时下降超过50%。在12周时，从所有检测对象中均分离出了奈韦拉平耐药病毒：血浆谷浓度均值（4.0微克/毫升[15.8微摩尔]）超过了耐药病毒的平均半数抑制浓度。48%的患者出现皮疹，6例患者皮疹成为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试验是合理的，以确定是否能够达到足以克服耐药病毒的药物血清水平。
