Sechaud Romain, Machineni Surendra, Tillmann Hanns-Christian, Hara Hisanori, Tan Xuemei, Zhao Rong, Ren Shuang, Hou Jie
Novartis Institutes for Biomedical Research, WSJ-386-12.48.13, Novartis Campus, 4002, Basel, Switzerland.
Novartis Healthcare Pvt. Ltd, Hyderabad, India.
Eur J Drug Metab Pharmacokinet. 2016 Dec;41(6):723-731. doi: 10.1007/s13318-015-0300-7.
Glycopyrronium is a once-daily long-acting muscarinic antagonist for the maintenance treatment of patients with chronic obstructive pulmonary disease. This study assessed the pharmacokinetics of inhaled glycopyrronium 50 µg once-daily for 14 days in healthy Chinese subjects.
In this open-label study, 12 Chinese healthy subjects (six males and six females; mean age 23.1 years [range 18-26 years]) were enrolled and completed the study. Glycopyrronium in plasma was determined using validated liquid chromatography-mass spectrometry method with a lower limit of quantification of 1.5 pg/mL. Plasma pharmacokinetic parameters were determined on Day 1 after first dose and on Day 14 (steady state) after last dose using non-compartmental analysis. Trough pharmacokinetic samples (Days 5, 7, 10 and 12) were collected. Safety was also assessed.
Glycopyrronium was rapidly absorbed into the systemic circulation after inhalation and its plasma concentrations decreased rapidly thereafter. Median time to reach maximum concentration (T ) was reached within 5 min after inhalation on both Days 1 and 14. Accumulation in the systemic exposure to glycopyrronium was observed from the time of first dose administration on Day 1 up to Day 14 and the observed accumulation ratio (R ) values of area under the plasma drug concentration-time curve [AUC] from time 0 to 24 h post-dose (AUC) and maximum plasma drug concentration (C ) (Day 14/Day 1) were 2.77 and 1.59, respectively. The elimination half-life (T ) was not reported. Mean effective half-life (T ) was 37.7 h. Pharmacokinetic steady state was reached after 5 days of daily dosing. One subject experienced dry mouth; otherwise glycopyrronium was well tolerated.
Comparison of systemic exposure to glycopyrronium in Chinese versus the non-Chinese population did not indicate clinically relevant ethnic differences. Multiple inhaled doses of glycopyrronium were safe and well tolerated.
格隆溴铵是一种每日一次的长效毒蕈碱拮抗剂，用于慢性阻塞性肺疾病患者的维持治疗。本研究评估了健康中国受试者每日一次吸入50μg格隆溴铵，连续14天的药代动力学情况。
在这项开放标签研究中，招募了12名中国健康受试者（6名男性和6名女性；平均年龄23.1岁[范围18 - 26岁]）并完成了研究。采用经过验证的液相色谱 - 质谱法测定血浆中的格隆溴铵，定量下限为1.5 pg/mL。使用非房室分析方法在首次给药后第1天和末次给药后第14天（稳态）测定血浆药代动力学参数。收集谷值药代动力学样本（第5、7、10和12天）。同时评估安全性。
吸入后格隆溴铵迅速吸收进入体循环，随后其血浆浓度迅速下降。在第1天和第14天，吸入后5分钟内均达到中位达峰时间（T）。从第1天首次给药至第14天观察到格隆溴铵全身暴露量有蓄积，给药后0至24小时血浆药物浓度 - 时间曲线下面积（AUC）和最大血浆药物浓度（C）的观察蓄积比（R）值（第14天/第1天）分别为2.77和1.59。未报告消除半衰期（T）。平均有效半衰期（T）为37.7小时。每日给药5天后达到药代动力学稳态。1名受试者出现口干；除此之外，格隆溴铵耐受性良好。
中国人群与非中国人群格隆溴铵全身暴露量的比较未显示出临床相关的种族差异。多次吸入格隆溴铵剂量安全且耐受性良好。
