Zhou Xiao-Jian, Pietropaolo Keith, Damphousse David, Belanger Bruce, Chen Jie, Sullivan-Bólyai John, Mayers Douglas
Idenix Pharmaceuticals Inc., One Kendall Square, Building 1400, Cambridge, MA 02139, USA.
Antimicrob Agents Chemother. 2009 May;53(5):1739-46. doi: 10.1128/AAC.01479-08. Epub 2009 Feb 17.
IDX899 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant strains of human immunodeficiency virus type 1 (HIV-1) and with a high genetic barrier to resistance. Single rising doses of 50 and 100 (given by use of a 50-mg capsule) and 200, 400, 800, and 1,200 mg (given by use of a 200-mg capsule) of IDX899 or matching placebo were administered sequentially to cohorts of healthy male subjects, followed by the administration of multiple doses of 800 mg once daily (QD) or 400 mg twice daily (BID) for 7 days. A single dose of 400 mg was also administered to a cohort of females. IDX899 was administered orally under fasted (50- to 400-mg doses) and then fed (> or = 200-mg doses) conditions. Exposure to IDX899 was dose proportional and comparable in males and females. With a different drug-to-excipient ratio, the 50-mg capsule led to a higher exposure but a shorter mean terminal half-life (t(1/2)) of 6.2 to 6.8 h. The 200-mg capsule resulted in a more sustained exposure with a longer mean t(1/2) of 7.9 to 14.6 h. Food enhanced absorption by approximately twofold, while it delayed the time to the maximum concentration. The mean concentration at 24 h following the administration of a single 200-mg dose under fed conditions exceeded the in vitro protein binding-adjusted 90% inhibitory concentration by fourfold. The levels of plasma exposure were similar between the single dosing and the repeat dosing with 800 mg QD and was approximately twofold higher with 400 mg BID. Mean steady-state trough levels were 0.9 microg/ml (range, 0.2 to 2.5 microg/ml) and 2.1 microg/ml (range, 0.5 to 4.5 microg/ml) for the 800-mg QD and 400-mg BID regimens, respectively. The level of excretion of unchanged drug in urine was negligible. IDX899 was well tolerated; and no serious adverse events, dose-dependent adverse events, or laboratory abnormalities were detected. These favorable safety and pharmacokinetic results support further clinical studies with patients with HIV-1 infection by the use of a QD regimen.
IDX899是一种新型非核苷类逆转录酶抑制剂（NNRTI），对1型人类免疫缺陷病毒（HIV-1）的野生型和耐NNRTI毒株具有强大的体外活性，且耐药基因屏障高。分别向多组健康男性受试者依次单次递增给予50和100mg（使用50mg胶囊）以及200、400、800和1200mg（使用200mg胶囊）的IDX899或匹配的安慰剂，随后每天一次（QD）给予多剂量800mg或每天两次（BID）给予400mg，持续7天。还向一组女性受试者单次给予400mg。IDX899在禁食（50至400mg剂量）然后进食（≥200mg剂量）条件下口服给药。IDX899的暴露量与剂量成比例，且在男性和女性中相当。由于药物与辅料比例不同，50mg胶囊导致更高的暴露量，但平均终末半衰期（t(1/2)）较短，为6.2至6.8小时。200mg胶囊导致暴露更持久，平均t(1/2)更长，为7.9至14.6小时。食物使吸收增加约两倍，同时延迟了达到最大浓度的时间。在进食条件下单次给予200mg剂量后24小时的平均浓度比体外蛋白结合调整后的90%抑制浓度高出四倍。单次给药和800mg QD重复给药后的血浆暴露水平相似，400mg BID给药后的暴露水平约高出两倍。800mg QD和400mg BID给药方案的平均稳态谷浓度分别为0.9μg/ml（范围为0.2至2.5μg/ml）和2.1μg/ml（范围为0.5至4.5μg/ml）。尿液中未变化药物的排泄量可忽略不计。IDX899耐受性良好；未检测到严重不良事件、剂量依赖性不良事件或实验室异常。这些良好的安全性和药代动力学结果支持对HIV-1感染患者使用QD给药方案进行进一步的临床研究。
