Peng A W, Hussey E K, Moore K H
Glaxo Wellcome, Inc., Research Triangle Park, North Carolina 27709, USA.
J Clin Pharmacol. 2000 Mar;40(3):242-9. doi: 10.1177/00912700022008900.
The pharmacokinetics of zanamivir were evaluated in subjects from three phase I single-center and two phase II multicenter, randomized, double-blind, multidose, placebo-controlled trials. A total of 96 phase I subjects received zanamivir (3.6 to 16 mg) intranasally two or six times daily for 4 to 5 days beginning 4 hours before or 1 to 2 days after inoculation with influenza virus. A total of 75 phase II subjects with influenza or a history of exposure to naturally occurring influenza virus were administered zanamivir as an intranasal spray (3.4 mg/nostril), inhaled powder (10 mg), or combination of intranasal and inhaled formulations twice daily for 5 days. Population parameters (including demographic factors, zanamivir formulation, infection-related variables, and concurrent medication use) were estimated by a nonlinear mixed-effect modeling software program (NONMEM) using a one-compartment model with first-order absorption and conditional estimation algorithm. Formulation and route of administration were the most significant factors affecting the pharmacokinetics of zanamivir. Relative bioavailability of the inhaled powder to the intranasal drops and spray was 2.3 and 1.6, respectively. No significant differences in pharmacokinetic parameters were observed when demographic variables, indices of infection, or concurrent medication use were considered in either phase I or phase II population analyses.
扎那米韦的药代动力学在三项I期单中心试验以及两项II期多中心、随机、双盲、多剂量、安慰剂对照试验的受试者中进行了评估。共有96名I期受试者在接种流感病毒前4小时或接种后1至2天开始，每天经鼻给予扎那米韦（3.6至16毫克），每日两次或六次，持续4至5天。共有75名患有流感或有自然感染流感病毒病史的II期受试者，以鼻喷雾剂（每侧鼻孔3.4毫克）、吸入粉雾剂（10毫克）或鼻内和吸入制剂联合使用的方式，每日两次，给予扎那米韦，持续5天。通过非线性混合效应建模软件程序（NONMEM），采用具有一级吸收和条件估计算法的单室模型，估计总体参数（包括人口统计学因素、扎那米韦制剂、感染相关变量和同时使用的药物）。制剂和给药途径是影响扎那米韦药代动力学的最重要因素。吸入粉雾剂相对于滴鼻剂和鼻喷雾剂的相对生物利用度分别为2.3和1.6。在I期或II期总体分析中，考虑人口统计学变量、感染指标或同时使用的药物时，未观察到药代动力学参数有显著差异。
