Cass L M, Efthymiopoulos C, Bye A
Clinical Pharmacology Division, Glaxo Wellcome Research and Development, Greenford, Middlesex, England.
Clin Pharmacokinet. 1999;36 Suppl 1:1-11. doi: 10.2165/00003088-199936001-00001.
The objective of these studies was to examine the clinical pharmacokinetics and safety of zanamivir, an influenza A and B virus neuraminidase inhibitor, when administered to healthy volunteers.
The safety, tolerability and pharmacokinetics of zanamivir administered by a number of routes were assessed in randomised, double-blind and placebo-controlled studies. The study of absolute oral bioavailability had an open design.
The participants in these studies were healthy male or female volunteers.
Zanamivir was administered as single or multiple doses by the intravenous, oral, inhaled (nebuliser and dry powder) and intranasal routes. Serum and urine samples were obtained for determination of pharmacokinetic parameters, and nasal washes and throat gargles were performed to assess drug concentrations in the nose and throat. Safety was evaluated by monitoring adverse events, vital signs and laboratory parameters.
Zanamivir was well tolerated at all doses by all routes; no serious adverse events were reported. The kinetics of zanamivir were linear with single intravenous doses up to 600 mg, and there was no evidence of modification in the kinetics after repeated twice-daily administration. Approximately 90% of zanamivir was excreted unchanged in the urine. The elimination of zanamivir from the serum was a first-order process with a half-life of approximately 2 hours and, at 16 L, the volume of distribution was similar to that of extracellular water. The absolute oral bioavailability of zanamivir was low, averaging 2%. After intranasal or oral inhaled administration, a median of 10 to 20% of the dose was systemically absorbed, with maximum serum concentrations generally reached within 1 to 2 hours. The median serum half-life ranged between 2.5 and 5.05 hours, suggesting that the elimination rate is limited by absorption. There was no evidence of modification in the kinetics after repeated inhaled administration.
Zanamivir is a well tolerated drug. The low level of absorption of the drug after inhaled administration results in low serum concentrations, and therefore there is modest systemic exposure to zanamivir after inhalation. Zanamivir is not metabolised, and the potential for clinically relevant drug-drug interactions is very low.
这些研究的目的是考察甲型和乙型流感病毒神经氨酸酶抑制剂扎那米韦在健康志愿者体内的临床药代动力学及安全性。
通过随机、双盲和安慰剂对照研究评估扎那米韦多种给药途径的安全性、耐受性和药代动力学。绝对口服生物利用度研究采用开放设计。
这些研究的参与者为健康男性或女性志愿者。
扎那米韦通过静脉、口服、吸入（雾化器和干粉）和鼻内途径单剂量或多剂量给药。采集血清和尿液样本以测定药代动力学参数，并进行鼻腔冲洗和咽喉含漱以评估鼻腔和咽喉中的药物浓度。通过监测不良事件、生命体征和实验室参数评估安全性。
扎那米韦在所有给药途径的所有剂量下耐受性良好；未报告严重不良事件。扎那米韦单次静脉给药剂量高达600mg时药代动力学呈线性，每日两次重复给药后药代动力学无改变迹象。约90%的扎那米韦以原形经尿液排泄。扎那米韦从血清中的消除为一级过程，半衰期约为2小时，分布容积为16L，与细胞外液相似。扎那米韦的绝对口服生物利用度较低，平均为2%。鼻内或口服吸入给药后，剂量的中位数有10%至20%被全身吸收，血清最高浓度一般在1至2小时内达到。血清半衰期中位数在2.5至5.05小时之间，表明消除速率受吸收限制。重复吸入给药后药代动力学无改变迹象。
扎那米韦是一种耐受性良好的药物。吸入给药后药物吸收水平较低导致血清浓度较低，因此吸入后扎那米韦的全身暴露量适中。扎那米韦不被代谢，临床相关药物相互作用的可能性非常低。
