Seaber E J, Peck R W, Smith D A, Allanson J, Hefting N R, van Lier J J, Sollie F A, Wemer J, Jonkman J H
Glaxo Wellcome Research and Development, Greenford, Middlesex, UK.
Br J Clin Pharmacol. 1998 Nov;46(5):433-9. doi: 10.1046/j.1365-2125.1998.00809.x.
Zolmitriptan (Zomig (formerly 311C90)) is a novel 5-HT1B/1D receptor agonist developed for the acute oral treatment of migraine. A highly sensitive LCMS-MS assay has been developed which allows quantification of plasma concentrations of zolmitriptan and its active metabolite, 183C91, after therapeutic doses. Two studies using this assay method were conducted to investigate the pharmacokinetics, including absolute bioavailability, of 2.5 and 5 mg oral doses of zolmitriptan in men and women, the dose-proportionality of 2.5, 5 and 10 mg doses and the effect of food on the pharmacokinetics of a 5 mg oral dose.
Two randomized, balanced, open-label, 4-period crossover studies were conducted in a total of 32 healthy volunteers. The first study determined the absolute bioavailability of 2.5 and 5 mg doses of zolmitriptan and compared the pharmacokinetics in men and women. The second study examined the dose-proportionality in pharmacokinetics after fasting doses of 2.5, 5 and 10 mg, and the effect of food on a 5 mg dose. Blood pressure, heart rate, ECG, clinical chemistry, haematology and adverse events were also monitored.
The mean (s.d.) absolute oral bioavailability was 0.41 (0.14 and 0.40) 0.09 after 2.5 mg and 0.48+/-0.14 and 0.36+/-0.07 after 5 mg in women and men, respectively. Without adjustment for bodyweight, plasma concentrations of zolmitriptan, but not 183C91, were higher in women than men. Mean (+/-s.d.) AUC was 32.7+/-10.1 and 60.2+/-26.8 ng ml(-1) h after 5 mg in men and women, respectively (95% CI for ratio 0.43-0.77). After 2.5 mg mean (+/-s.d.) AUC was 18.4+/-5.4 and 23.1+/-9.9 ng ml(-1) h in men and women, respectively (95% CI for ratio 0.61-1.09). However, these differences were of no clinical significance. Cmax and AUC of oral zolmitriptan were dose-proportional and there was a 13 and 16% fall in mean zolmitriptan Cmax and AUC, respectively, when administered after food. Adverse effects were minor, predominantly mild and transient, and there were no clinically significant effects on ECG, blood pressure, or laboratory parameters.
At therapeutic doses zolmitriptan has good oral bioavailability in healthy volunteers and has dose-proportional pharmacokinetics that are not affected by food to any clinically relevant extent.
佐米曲普坦（佐米格，原称311C90）是一种新型5 - HT1B/1D受体激动剂，用于偏头痛的急性口服治疗。已开发出一种高灵敏度的液相色谱 - 质谱联用（LCMS - MS）测定法，可在治疗剂量后定量测定血浆中佐米曲普坦及其活性代谢物183C91的浓度。进行了两项使用该测定方法的研究，以调查2.5毫克和5毫克口服剂量的佐米曲普坦在男性和女性中的药代动力学，包括绝对生物利用度、2.5毫克、5毫克和10毫克剂量的剂量比例性以及食物对5毫克口服剂量药代动力学的影响。
在总共32名健康志愿者中进行了两项随机、平衡、开放标签、4期交叉研究。第一项研究确定了2.5毫克和5毫克剂量佐米曲普坦的绝对生物利用度，并比较了男性和女性的药代动力学。第二项研究检查了空腹服用2.5毫克、5毫克和10毫克剂量后药代动力学的剂量比例性以及食物对5毫克剂量的影响。还监测了血压、心率、心电图、临床化学、血液学和不良事件。
女性服用2.5毫克后平均（标准差）绝对口服生物利用度为0.41（0.14），男性服用5毫克后分别为0.48±0.14和0.36±0.07。未按体重调整时，女性血浆中佐米曲普坦的浓度高于男性，但183C91的浓度并非如此。男性和女性服用5毫克后平均（±标准差）曲线下面积（AUC）分别为32.7±10.1和60.2±26.8 ng/ml·h（比值的95%置信区间为0.43 - 0.77）。服用2.5毫克后，男性和女性的平均（±标准差）AUC分别为18.4±5.4和23.1±9.9 ng/ml·h（比值的95%置信区间为0.61 - 1.09）。然而，这些差异无临床意义。口服佐米曲普坦的峰浓度（Cmax）和AUC与剂量成比例，进食后服用时，佐米曲普坦的平均Cmax和AUC分别下降13%和16%。不良反应轻微，主要为轻度且短暂，对心电图、血压或实验室参数无临床显著影响。
在治疗剂量下，佐米曲普坦在健康志愿者中具有良好的口服生物利用度，其药代动力学与剂量成比例，且在临床上任何相关程度上均不受食物影响。
