On the population pharmacokinetics and the enterohepatic recirculation of inhaled formoterol 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 develop a population pharmacokinetic (PK) model for describing the absorption kinetics and enterohepatic recirculation (EHC) of formoterol (FOR) following inhaled administration.
Methods: Plasma concentration (C) – time (t) data of FOR were obtained from a single dose, 2x2 bioequivalence study comparing two dry powder inhalers (DPIs). The study included a number of ninety, controlled or partly controlled, male and female patients under fasting conditions, with activated charcoal administration. Non-linear mixed-effect modeling was applied and a PK model able to describe the kinetics of FOR was developed. Different methodologies were tested, including multi-compartment models with an enterohepatic loop using first or zero order transfer rate constants, sine function models for gallbladder control, gallbladder emptying time, presence or absence of bile elimination. 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: The FOR C-t profiles were best described by a two-compartment disposition model linked to bile and gastrointestinal (GI) compartments. Elimination from the central and bile compartments was considered to follow first order kinetics. The final model included an EHC loop with the introduction of two additional compartments (i.e., bile and GI) linked by first order kinetics and a gallbladder emptying time interval. The model was finally parameterized in terms of the lung absorption rate constant (KL =15.8 h-1), the apparent volume of distribution in the central (Vc/F=873 L) and peripheral (Vp/F=1,460 L) compartment, the apparent clearance from the central compartment (CL/F=110 L/h), the inter-compartmental clearance (Q/F =2,850 L/h), the transfer rate constant to bile (Kb=0.36 h-1), the excretion rate constant from bile to the intestine (Kg=0.57 h-1), the GI absorption (Ka=0.28 h-1) and fecal elimination (Kfec=0.02h-1) rate constants. The application of a combined error model led to the optimum performance. No significant covariate was found and no difference in the performances of the two DPIs was observed.
Conclusions: A population PK model with an EHC component was found to fit suitably the plasma C-t data of inhaled FOR. Several EHC scenarios were developed and their performance was evaluated in terms of physiological soundness and goodness-of-fit criteria.
