PHARMACOKINETICS OF NEVIRAPINE - INITIAL SINGLE-RISING-DOSE STUDY IN HUMANS
PHARMACOKINETICS OF NEVIRAPINE - INITIAL SINGLE-RISING-DOSE STUDY IN HUMANS
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DOI：
10.1128/aac.37.2.178
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发表时间：
1993-02-01
影响因子：
4.9
通讯作者：
KEIRNS, JJ
中科院分区：
文献类型：
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作者：
CHEESEMAN, SH;HATTOX, SE;KEIRNS, JJ
奈韦拉平是一种人类免疫缺陷病毒1型（HIV-1）逆转录酶的非核苷抑制剂，在一项初步研究中首次对人体给药，旨在研究21名HIV-1感染者单次给药后药物的药代动力学和耐受性。该研究遵循平行设计。每组3名受试者的不同组从最低剂量开始依次接受7个剂量水平（2.5至400 mg）中的一个。每例受试者仅接受一次给药。所有剂量的奈韦拉平片剂均被迅速吸收。血浆峰浓度通常在给药后90 min内达到。在3 - 12 h或24 - 28 h之间也观察到次要峰，后者主要见于接受较高剂量的受试者。24小时后，血浆浓度以对数线性方式下降。除1例受试者外，所有受试者的终末半衰期和平均滞留时间均超过24 h，表明该人群的分布时间延长。血浆峰浓度和血浆浓度-时间曲线下面积均随剂量从2.5 mg增加至200 mg而成比例增加;然而，在400 mg剂量水平下，在这少数受试者中，血浆峰浓度和血浆浓度-时间曲线下面积的增加似乎低于比例。这一观察结果可能是由于最高剂量下清除率增加或吸收率降低，或剂量之间吸收或清除率的群体差异所致。计划进行交叉设计的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 mg剂量可达到完全抑制人T细胞培养物中野生型HIV-1复制所需的血浆谷浓度范围。
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.