Single- and multiple-dose pharmacokinetics of the peripheral non-narcotic antitussive moguisteine in healthy Chinese volunteers

被引:1
作者
Gou, Zhong-Ping [1 ]
Zheng, Li [1 ]
Wang, Ying [1 ]
Feng, Ping [1 ]
Xiang, Jin [1 ]
机构
[1] Sichuan Univ, Inst Drug Clin Trials, West China Hosp, Chengdu 610041, Sichuan, Peoples R China
关键词
Moguisteine; Metabolite; Antitussive drug; Pharmacokinetics; Healthy subjects; Randomized; Crossover study; OVER-THE-COUNTER; ACUTE COUGH; EFFICACY; SAFETY;
D O I
10.1016/j.ejps.2019.01.029
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background: Moguisteine is a non-narcotic peripheral antitussive drug that has been effective and well-tolerated in clinical studies. The aim of the present work was to investigate the pharmacokinetics of moguisteine given as single or multiple doses to healthy Chinese subjects. Methods: In Stages 1-3 of this study, 12 healthy Chinese subjects (6 males and 6 females) participated in a randomized, open-label, single-dose, 3-period, 3-way crossover study, with a 24-h washout period between each treatment. Eligible subjects were randomized to receive a single dose of 100, 200 or 400 mg moguisteine. Blood was sampled before and up to 10 h after administration. In those receiving 200 mg moguisteine, urine was sampled at intervals of 0-2, 2-4, 4-6, 6-10, and 10-24 h. In Stage 4, subjects received a moguisteine tablet containing 200 mg three times daily for five consecutive days. Blood was sampled for up to 10 h after the last dose. HPLC-tandem mass spectrometry was used to determine concentrations of the moguisteine metabolite M1 in serum, while HPLC-UV was used to determine concentrations of M1 in urine. Safety of the dosing schedules was assessed based on physical examination, recording of adverse events, 12-lead electrocardiography, and laboratory tests. Results: All subjects completed all four stages of the study. M1 was detectable at the shortest time points after moguisteine administration; the time to achieve peak concentration was 0.5-1.0 h in single dosing and 1.5 h in multiple dosing. Elimination half-life (t(1/2)) was 0.91-1.54 h in single dosing and 1.57 h in multiple dosing. AUC increased roughly proportionally with dose, while C(max )increased much more gradually with dose. During 5-day dosing of three tablets per day, a steady state concentration was reached on day 3, and the mean accumulation ratio was 0.87. At 24 h after a single dose of 200 mg moguisteine, approximately 34.0% of the resulting M1 was recovered in urine. Pharmacokinetics of moguisteine did not differ significantly between men and women, except among those receiving a single dose of 100 mg (P < 0.05). Mild adverse events (nausea, loose stool, abdominal distention, or dizziness) occurred in six subjects and resolved without treatment, while no serious adverse events were observed. Conclusion: Moguisteine was safe and well-tolerated by our healthy subjects, and it exhibited dose linearity but not proportionality when a single dose of 100-400 mg was given. M1 did not accumulate in subjects after multiple doses of moguisteine.
引用
收藏
页码:166 / 172
页数:7
相关论文
共 26 条
[1]  
ADAMS R, 1993, ADV THER, V10, P263
[2]  
[Anonymous], 2000, Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects
[3]  
AVERSA C, 1993, DRUG EXP CLIN RES, V19, P273
[4]   Stereoselective pharmacokinetics of moguisteine metabolites in healthy subjects [J].
Bernareggi, A ;
Crema, A ;
Carlesi, RM ;
Castoldi, D ;
Ratti, E ;
Renoldi, MI ;
Ratti, D ;
Ceserani, R ;
Tognella, S .
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1995, 20 (04) :263-270
[5]  
Bernareggi A., 1993, EUR J DRUG METAB PH, V18, P163
[6]   Developing antitussives: The ideal clinical trial [J].
Birring, Surinder S. .
PULMONARY PHARMACOLOGY & THERAPEUTICS, 2009, 22 (02) :155-158
[7]   Cough suppressant protussive therapy and pharmacologic - ACCP evidence-based clinical practice guidelines [J].
Bolser, DC .
CHEST, 2006, 129 (01) :238S-249S
[8]   Currently available cough suppressants for chronic cough [J].
Chung, Kian Fan .
LUNG, 2008, 186 (Suppl 1) :S82-S87
[9]  
DELDONNO M, 1994, DRUG INVEST, V7, P93
[10]  
Di Giovine S., 1992, PHARMACOKINETICS MET, P81