Xceleron Ltd, Innovation Way, York, UK.
Clin Pharmacokinet. 2012 Apr 1;51(4):237-46. doi: 10.2165/11597070-000000000-00000.
The aim of this crossover human male volunteer study was to investigate the utility of microdosing in the investigation of drug-drug interactions.
A mixture of midazolam, tolbutamide, caffeine and fexofenadine were administered as a microdose (25 μg each) before and after administration of a combined pharmacological dose of ketoconazole (400 mg) and fluvoxamine (100 mg) to inhibit P-glycoprotein and metabolism by cytochrome P450 (CYP) 1A2, CYP3A4 and CYP2C9.
When administered alone, pharmacokinetics for all four microdosed compounds scaled well with those reported for therapeutic doses and with previously performed microdose studies. The pharmacokinetics of each compound administered as a microdose were significantly altered after the administration of ketoconazole and fluvoxamine, showing statistically significant (p < 0.01) 12.8-, 8.1- and 3.2-fold increases in the area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) for midazolam, caffeine and fexofenadine, respectively. A 1.8-fold increase (not statistically significant) in AUC(∞) was observed for tolbutamide. The changes in pharmacokinetics mediated by ketoconazole and fluvoxamine were quantitatively consistent with previously reported, non-microdose, drug-drug interaction data from studies including the same compounds.
The initial data reported here demonstrate the utility of microdosing to investigate the risk of development drugs being victims of drug-drug interactions.
本交叉人体男性志愿者研究的目的是研究微剂量在药物相互作用研究中的应用。
咪达唑仑、甲苯磺丁脲、咖啡因和非索非那定混合物作为微剂量(各 25μg)给药,然后给予酮康唑(400mg)和氟伏沙明(100mg)联合给药,以抑制 P-糖蛋白和细胞色素 P450(CYP)1A2、CYP3A4 和 CYP2C9 的代谢。
当单独给药时,所有四种微剂量化合物的药代动力学与治疗剂量报告的药代动力学以及以前进行的微剂量研究很好地吻合。在给予酮康唑和氟伏沙明后,每个化合物作为微剂量给药的药代动力学均发生显著改变,咪达唑仑、咖啡因和非索非那定的 AUC(∞)分别显示出统计学上显著(p<0.01)的 12.8、8.1 和 3.2 倍增加,甲苯磺丁脲的 AUC(∞)增加 1.8 倍(无统计学意义)。酮康唑和氟伏沙明介导的药代动力学变化与包括相同化合物的先前非微剂量药物相互作用研究中报告的先前报道的数据在数量上是一致的。
这里报告的初步数据表明微剂量在研究药物相互作用风险方面的应用。