Konstantina Soulele, Panos Macheras, Vangelis Karalis
Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
Objectives: To apply population pharmacokinetic modeling in order to describe the concentration-time (C-t) profile of salmeterol in asthmatic patients after administration of two dry powder inhalers (DPI).
Methods: Salmeterol plasma C-t data were obtained from a single dose 2×4 bioequivalence study comparing two dry powder inhalers in 48 asthmatic male and female subjects under fasting conditions, without co-administration of activated charcoal. Non-linear mixed-effect modeling was applied to the obtained C-t dataset. Since, no charcoal was administered, apart from the pulmonary, gastrointestinal (GI) absorption could also occur. A pharmacokinetic model capable of describing the parallel lung and GI absorption was developed. Many residual error models were tested, whereas age, gender, body weight, and height were explored as potential covariates. The entire computational work was implemented in Monolix v.4.3.3.
Results: A two-compartment disposition model with first order absorption from the GI and very rapid absorption from lungs (like IV bolus) was found to describe successfully the C-t profiles of all patients. Elimination was considered to take place in the central compartment following first order kinetics. The model was parameterized in terms of the GI absorption rate constant (Ka), apparent volume of distribution in the central (Vc/F) and the peripheral (Vp/F) compartment, as well as apparent clearance (CL/F) and inter-compartmental clearance (Q/F). The relative fraction of dose absorbed (Rpo) through the GI was set as a parameter estimated by the optimization process. The application of a proportional error model led to the optimum performance. The following pharmacokinetic parameters were estimated: Ka = 0.325 h-1, Rpo = 0.85, Vc/F = 218 L, Vp/F = 2970 L, Q/F = 339 L/h, and CL/F = 408 L/h. Gender was found a significant covariate on salmeterol clearance. Men were found to exhibit higher clearance than women, a finding that is in agreement with that observed in healthy subjects [1]. Body weight was also found a significant covariate on the volume of distribution of the central compartment. As body weight increases, the value of this parameter also rise. No difference in the performances of the two DPIs was observed.
Conclusions: A population pharmacokinetic model, with parallel GI and lung absorption was found to describe successfully the C-t profile of salmeterol in asthmatic patients. Women exerted less capability to eliminate salmeterol than men.
References:
[1] Soulele K, Macheras P, Silvestro L, Rizea Savu S, Karalis V. Population pharmacokinetics of fluticasone propionate/salmeterol using two different dry powder inhalers. Eur J Pharm Sci (2015) 80: 33-42.
Reference: PAGE 25 (2016) Abstr 5874 [www.page-meeting.org/?abstract=5874]
Poster: Drug/Disease modeling - Other topics