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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.

Ezetimibe is a potent cholesterol absorption inhibitor, with an erratic pharmacokinetic (PK) profile, attributed to an extensive enterohepatic recirculation (EHC). The aim of this study was to develop a population PK model able to adequately characterize the complex distribution processes of total ezetimibe. The analysis was performed on the individual concentration-time data obtained from 28 healthy subjects who participated in a bioequivalence study comparing two oral ezetimibe formulations. The population PK analysis was performed using nonlinear mixed effect modeling, where different EHC models were developed and evaluated for their performance. Total ezetimibe pharmacokinetics was best described by a four-compartment model featuring EHC through the inclusion of an additional gallbladder compartment, which was assumed to release drug at specific time-intervals consistent with food intake. The final PK model was able to adequately estimate the population pharmacokinetic parameters and to allow for a formal characterization of the pharmacokinetic profile and the secondary peaks due to enterohepatic recirculation.