Russell T, Stoltz M, Weir S
Department of Clinical Pharmacokinetics, Hoechst Marion Roussel Inc., Kansas City, MO 64137-1405, USA.
Clin Pharmacol Ther. 1998 Dec;64(6):612-21. doi: 10.1016/S0009-9236(98)90052-2.
Fexofenadine is a selective, nonsedating H1-receptor antagonist that relieves symptoms of allergic conditions.
Two randomized, double-blind, parallel-group, placebo-controlled dose-escalation studies were performed in healthy men to determine the maximum tolerated oral dose, pharmacokinetics, pharmacodynamics, and safety of fexofenadine hydrochloride. In the first study, 87 subjects (6 in the active drug group and 2 in the placebo group) received single oral doses of fexofenadine hydrochloride ranging from 10 to 800 mg or placebo. In the second study, 32 subjects (3 in the active drug group and 1 in the placebo group) received multiple fexofenadine hydrochloride doses ranging from 20 to 690 mg or placebo twice daily for 28 1/2 days. Serial plasma and urine samples were collected. Fexofenadine concentrations were determined by HPLC and fluorescence. Wheal and flare response to intradermal histamine was used to evaluate antihistaminic activity.
Fexofenadine hydrochloride was rapidly absorbed, reaching peak concentrations in 0.83 to 1.33 hours. Single-dose mean concentration ranged from 46 to 6383 ng/mL, and steady-state maximum plasma concentration ranged from 58 to 4677 ng/mL. Mean area under the plasma concentration-time curve was approximately proportional to dose. Oral clearance, renal clearance, and cumulative percent of drug excreted in urine were similar after single and multiple doses and were generally constant over the dose range studied. Inhibition of skin wheal and flare was shown for single doses of 40 mg and higher and for all multiple doses. No fexofenadine dose-related trends or apparent differences from placebo were found for any safety parameter.
Fexofenadine hydrochloride was well tolerated at oral doses up to 11 times the recommended therapeutic dose. In addition, fexofenadine hydrochloride showed significant antihistaminic activity and dose-proportional pharmacokinetics over a wide dosing range.
非索非那定是一种选择性、非镇静性H1受体拮抗剂，可缓解过敏症状。
在健康男性中进行了两项随机、双盲、平行组、安慰剂对照的剂量递增研究，以确定盐酸非索非那定的最大耐受口服剂量、药代动力学、药效学和安全性。在第一项研究中，87名受试者（活性药物组6名，安慰剂组2名）接受了10至800毫克盐酸非索非那定或安慰剂的单次口服剂量。在第二项研究中，32名受试者（活性药物组3名，安慰剂组1名）接受了20至690毫克盐酸非索非那定或安慰剂的多次剂量，每日两次，共28.5天。采集了系列血浆和尿液样本。通过高效液相色谱法和荧光法测定非索非那定浓度。采用皮内组胺风团和潮红反应评估抗组胺活性。
盐酸非索非那定吸收迅速，在0.83至l.33小时内达到峰值浓度。单剂量平均浓度范围为46至6383纳克/毫升，稳态最大血浆浓度范围为58至4677纳克/毫升。血浆浓度-时间曲线下的平均面积与剂量大致成正比。单次和多次给药后，口服清除率、肾清除率和尿液中药物排泄的累积百分比相似，并且在所研究的剂量范围内通常是恒定的。单剂量40毫克及以上以及所有多剂量均显示出对皮肤风团和潮红的抑制作用。在任何安全参数方面，均未发现非索非那定剂量相关趋势或与安慰剂有明显差异。
盐酸非索非那定在高达推荐治疗剂量11倍的口服剂量下耐受性良好。此外，盐酸非索非那定在广泛的给药范围内显示出显著的抗组胺活性和剂量成正比的药代动力学。
