Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects
Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects
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DOI：
10.1006/pupt.1999.0217
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发表时间：
1999-01-01
影响因子：
3.2
通讯作者：
Jusko, WJ
中科院分区：
文献类型：
--
作者：
Gumbhir-Shah, K;Kellerman, DJ;Jusko, WJ
本研究的目的是比较单次累积剂量的活性(R)-沙丁胺醇作为单一对映体或外消旋混合物吸入轻度至中度哮喘患者的药代动力学、药效学和安全性。这是一项双盲、交叉、累积剂量、随机研究，所有受试者通过雾化方式接受四剂量1.25 mg (R)-沙丁胺醇或2.5 mg （RS-）沙丁胺醇。通过非区室分析和模型拟合确定药代动力学参数。测量FEV1、血浆钾、血糖、心率和QTc间期的变化。钾和葡萄糖数据符合间接反应药效学模型。使用数据描述符评估心率和QTc数据。(R)-沙丁胺醇与(RS)-沙丁胺醇的药代动力学无显著差异，AUC值分别为11.90 +/- 4.37和11.47 +/- 2.88 ng.h/ml。约2h的t（max）反映的是连续给药，而不是延迟吸收。t（1/2）平均约为3.5 h。(S)-沙丁胺醇在t（1/2）约为5 h时AUC为48.46 +/- 12.11 ng.h/ml。FEV1的变化在初始升高后达到平台期，10 h后未恢复到药前值。哮喘受试者吸入(R)-沙丁胺醇和(RS)-沙丁胺醇后的(R)-沙丁胺醇暴露量相同。包括FEV1在内的几种药理学反应也相似，两种治疗都没有独特的安全性问题。
Objectives of this study were to compare the pharmacokinetics, pharmacodynamics and safety of single cumulative doses of active (R)-salbutamol given either as the single enantiomer or racemic mixture by inhalation to subjects with mild to moderate asthma. This was a double-blind, crossover, cumulative-dose, randomized study where all subjects received either four doses of 1.25 mg of (R)-salbutamol or 2.5 mg of racemic (RS-) salbutamol by nebulization. The pharmacokinetic parameters were determined by noncompartmental analysis and model-fitting. Changes in FEV1, plasma potassium, plasma glucose, heart rate, and QTc interval were measured. The potassium and glucose data were fitted to indirect response pharmacodynamic models. The heart rate and QTc data were evaluated using data descriptors. No significant differences in pharmacokinetics of (R)-salbutamol given as either (R)- or (RS)-salbutamol were found with AUC values of 11.90 +/- 4.37 and 11.47 +/- 2.88 ng.h/ml. The t(max) of about 2 h reflected serial dosing rather than delayed absorption. The t(1/2) averaged about 3.5 h. The (S)-salbutamol showed AUC of 48.46 +/- 12.11 ng.h/ml with a t(1/2) of about 5 h. The changes in FEV1 reached a plateau after an initial increase and did not return to pre-drug values for 10 h. All pharmacodynamic parameters were similar whether (R)- or (RS)-salbutamol was given. The exposure to (R)-salbutamol was identical after inhalation of (R) -and (RS)-salbutamol by subjects with asthma. Several pharmacological responses including FEV1 were also similar and there were no unique safety concerns with either treatment.