Soulele Konstantina, Macheras Panos, Karalis Vangelis
Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, University Campus, Athens, 157 84, Greece.
Biopharm Drug Dispos. 2017 Oct;38(7):407-419. doi: 10.1002/bdd.2077. Epub 2017 Jul 12.
Salmeterol (SAL) is a long-acting β2-adrenergic agonist, which is widely used in the therapy of asthma. The aim of this study was to investigate the pharmacokinetics (PK) of inhaled salmeterol in asthma patients using two different dry powder inhalers. This analysis was based on data from 45 subjects who participated in a two-sequence, four-period crossover bioequivalence (BE) study after single administration of the test (T) and reference (R) products. In order to mimic more closely the real treatment conditions, activated charcoal was not co-administered. Plasma concentration-time (C-t) data were initially analysed using classic non-compartmental PK approaches, while the main objective of the study was to apply population PK modeling. The relative fraction of the dose absorbed via the lungs (R ) was set as a parameter in the structural model. The plasma C-t profiles of salmeterol showed a biphasic time course indicating a parallel pulmonary and gastrointestinal (GI) absorption. A two-compartment disposition model with first order absorption from the GI and very rapid absorption from lungs (like an i.v. bolus) was found to describe successfully the C-t profiles of salmeterol. The estimated R value was 13% suggesting a high gut deposition of inhaled salmeterol. Women were found to exert less capability to eliminate salmeterol than men, while body weight (in allometric form) was found to be an important covariate on the peripheral volume of distribution.
沙美特罗（SAL）是一种长效β2肾上腺素能激动剂，广泛用于哮喘治疗。本研究的目的是使用两种不同的干粉吸入器，研究哮喘患者吸入沙美特罗的药代动力学（PK）。该分析基于45名受试者的数据，这些受试者在单次服用试验（T）和参比（R）产品后，参与了一项两序列、四周期交叉生物等效性（BE）研究。为了更接近真实治疗情况，未同时给予活性炭。血浆浓度-时间（C-t）数据最初使用经典的非房室PK方法进行分析，而该研究的主要目的是应用群体PK建模。通过肺部吸收的剂量相对分数（R）被设定为结构模型中的一个参数。沙美特罗的血浆C-t曲线显示出双相时间过程，表明肺部和胃肠道（GI）吸收平行。发现一个二房室处置模型成功地描述了沙美特罗的C-t曲线，该模型具有从胃肠道的一级吸收和从肺部的非常快速的吸收（类似于静脉推注）。估计的R值为13%，表明吸入的沙美特罗在肠道沉积较多。发现女性消除沙美特罗的能力低于男性，而体重（以异速生长形式）是外周分布容积的一个重要协变量。
