Cheeseman S H, Hattox S E, McLaughlin M M, Koup R A, Andrews C, Bova C A, Pav J W, Roy T, Sullivan J L, Keirns J J
Department of Medicine, University of Massachusetts Medical School, Worcester 01655.
Antimicrob Agents Chemother. 1993 Feb;37(2):178-82. doi: 10.1128/AAC.37.2.178.
Nevirapine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, was administered for the first time to humans in a pilot study designed to investigate the pharmacokinetics and tolerance of the drug following single-dose administration to 21 HIV-1-infected individuals. The study followed a parallel design. Different groups of three subjects each were given one of seven dose levels (2.5 to 400 mg) in sequential order, starting with the lowest dose. Each subject received only one dose. Nevirapine was rapidly absorbed at all doses from a tablet formulation. Peak concentrations in plasma were generally achieved within 90 min of dose administration. Secondary peaks were also noted between 3 and 12 h or between 24 and 28 h, the latter being noted mainly in subjects receiving the higher doses. After 24 h, concentrations in plasma declined in a log-linear fashion. The terminal half-life and mean residence time exceeded 24 h in all but one subject, indicating a prolonged disposition time in this population. Both peak concentrations in plasma and areas under the plasma concentration-time curves increased proportionally with increasing dose from 2.5 to 200 mg; however, the increase in the peak concentration in plasma and the area under the plasma concentration-time curve appeared to be less than proportional at the 400-mg dose level in this small number of subjects. This observation may be due to increased clearance or decreased absorption at the highest dose or population differences in absorption or clearance between doses. Studies with a cross-over design are planned to resolve these issues. The pharmacokinetic characteristics of nevirapine are appropriate for once-daily administration. A daily 12.5-mg dose is predicted to achieve trough concentrations in plasma in the range required to totally inhibit replication of wild-type HIV-1 in human T-cell culture.
奈韦拉平是一种人免疫缺陷病毒1型（HIV-1）逆转录酶的非核苷抑制剂，在一项旨在研究该药物对21名HIV-1感染个体单剂量给药后的药代动力学和耐受性的试点研究中首次用于人体。该研究采用平行设计。每组三名受试者按顺序接受七个剂量水平（2.5至400毫克）中的一个，从最低剂量开始。每个受试者仅接受一剂。奈韦拉平从片剂剂型在所有剂量下均能快速吸收。血浆中的峰值浓度一般在给药后90分钟内达到。在3至12小时或24至28小时之间也观察到次要峰值，后者主要在接受较高剂量的受试者中出现。24小时后，血浆浓度呈对数线性下降。除一名受试者外，所有受试者的终末半衰期和平均驻留时间均超过24小时，表明该人群中的处置时间延长。血浆中的峰值浓度和血浆浓度-时间曲线下面积在2.5至200毫克剂量范围内均随剂量增加而成比例增加；然而，在这少数受试者中，400毫克剂量水平下血浆峰值浓度和血浆浓度-时间曲线下面积的增加似乎小于成比例增加。这一观察结果可能是由于最高剂量下清除率增加或吸收减少，或不同剂量之间吸收或清除的人群差异所致。计划进行交叉设计研究以解决这些问题。奈韦拉平的药代动力学特征适合每日一次给药。预计每日12.5毫克的剂量可使血浆中的谷浓度达到在人T细胞培养中完全抑制野生型HIV-1复制所需的范围。
