Sechaud Romain, Renard Didier, Zhang-Auberson Lixin, Motte Stephan de la, Drollmann Anton, Kaiser Guenther
Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
Int J Clin Pharmacol Ther. 2012 Feb;50(2):118-28. doi: 10.5414/cp201612.
NVA237 (glycopyrronium bromide) is a once-daily longacting muscarinic antagonist (LAMA) in development for the treatment of chronic obstructive pulmonary disease (COPD). This study investigated the pharmacokinetics (PK) of NVA237 following single and repeated once-daily inhalation in mild-tomoderate COPD patients.
In this double-blind, parallel-group study, COPD patients were randomized to a 14-day treatment with NVA237 (25, 50, 100 or 200 μg) or placebo. Plasma concentration-time profiles and urinary excretion of NVA237 were determined on Days 1 and 14.
The median time to reach maximal plasma concentration (tmax) was 5 or 6.5 min postinhalation. At steady state (Day 14), total and maximum systemic exposure (AUC0-24, Cmax) to NVA237 and urinary excretion of unchanged drug (Ae0-24) was approximately dose proportional over the 50 - 200 μg dose range. The average exposure was 1.4- to 1.7- fold higher on Day 14 compared with Day 1. The mean terminal elimination half-life (t1/2) of NVA237 ranged between 13 and 22 h. Steady-state plasma concentrations were reached within 1 week of treatment. Renal clearance (CLR) was similar across doses both after single and repeated dosing, ranging between 17.4 and 20.6 l/h. Urinary excretion of NVA237 enantiomers ([3S,2R]- and [3R,2S]-stereoisomers) was similar with respect to the amount excreted within 24 h and the excretion rate.
The pharmacokinetics of NVA237 were consistent between doses with limited systemic accumulation at steady state after repeated once-daily inhalation.
NVA237（格隆溴铵）是一种每日一次的长效毒蕈碱拮抗剂（LAMA），正处于研发阶段，用于治疗慢性阻塞性肺疾病（COPD）。本研究调查了轻度至中度COPD患者单次及每日一次重复吸入NVA237后的药代动力学（PK）情况。
在这项双盲、平行组研究中，COPD患者被随机分为接受NVA237（25、50、100或200μg）或安慰剂治疗14天。在第1天和第14天测定NVA237的血浆浓度-时间曲线和尿排泄情况。
达到最大血浆浓度（tmax）的中位时间为吸入后5或6.5分钟。在稳态（第14天）时，在50 - 200μg剂量范围内，NVA237的总全身暴露量和最大全身暴露量（AUC0-24、Cmax）以及原形药物的尿排泄量（Ae0-24）与剂量大致成比例。与第1天相比，第14天的平均暴露量高1.4至1.7倍。NVA237的平均终末消除半衰期（t1/2）在13至22小时之间。治疗1周内达到稳态血浆浓度。单次和重复给药后，各剂量的肾清除率（CLR）相似，范围在17.4至20.6 l/h之间。NVA237对映体（[3S,2R]-和[3R,2S]-立体异构体）在24小时内的排泄量和排泄率相似。
NVA237的药代动力学在各剂量之间具有一致性，每日一次重复吸入后稳态时全身蓄积有限。
