Population pharmacokinetic analysis of inhaled budesonide in asthma patients
Konstantina Soulele (1), Panos Macheras (1,2), Vangelis Karalis (1)
(1) Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Greece, (2) Pharma-Informatics Unit of Research & Innovation Center ATHENA
Objectives: To apply population pharmacokinetic modeling in order to describe the absorption and distribution kinetics of budesonide in asthma patients after administration of two different dry powder inhalers (DPI).
Methods: Budesonide plasma concentration (C) – time (t) data were obtained from a single dose, 2x2 bioequivalence study comparing two dry powder inhalers in 90 controlled or partly controlled asthma male and female patients under fasting conditions, with co-administration of activated charcoal. Non-linear mixed-effect modeling was applied and a pharmacokinetic model capable of describing the parallel fast and slow lung absorption of budesonide was developed. Several error models were tested, whereas the period and treatment effects, as well as, demographic characteristics were explored as potential covariates. The entire computational work was implemented in Monolix 4.3.3.
Results: A two-compartment disposition model with two parallel first order absorption processes (fast and slow) from the lungs was found to describe successfully the C-t profiles of budesonide. Elimination was considered to take place in the central compartment following first order kinetics. The model was parameterized in terms of the fast (Kaf) and slow (Kas) lung absorption rate constants, the apparent volume of distribution in the central (Vc/F) and peripheral (Vp/F) compartments, the apparent clearance (CL/F), the inter-compartmental clearance (Q/F), the relative fractions of dose absorbed either slowly (Rslow) or fast (Rfast) through the lungs, and the Rfast/Rslow ratio (z). The application of a combined error model led to the optimum performance. The following estimates were found for the pharmacokinetic parameters: Kaf = 19.6 h-1, Kas = 0.11 h-1, Rslow = 0.63, z = 0.27, Vc/F = 271 L, Vp/F = 218 L, Q/F = 305 L/h, and CL/F = 185 L/h. Gender was found a significant covariate on Kas and Vp/F, with men exhibiting higher Kas and lower Vp/F compared to women. No difference in the performances of the two DPIs was observed.
Conclusions: A population pharmacokinetic model, with two parallel lung absorption processes was found to describe successfully the C-t profile of budesonide in asthma patients. Following an initial fast pulmonary absorption, a second slower absorption phase was evident most probably attributed to the lung deposition (central/peripheral) of budesonide and the formation of fatty acid conjugated esters in the airways.
