Combined in Vitro-in Silico Approach to Predict Deposition and Pharmacokinetics of Budesonide Dry Powder Inhalers
- PDF / 1,517,409 Bytes
- 19 Pages / 595.276 x 790.866 pts Page_size
- 64 Downloads / 212 Views
RESEARCH PAPER
Combined in Vitro-in Silico Approach to Predict Deposition and Pharmacokinetics of Budesonide Dry Powder Inhalers Conor A. Ruzycki 1
1
1
1
& Brynn Murphy & Hafeez Nathoo & Warren H. Finlay & Andrew R. Martin
1
Received: 4 March 2020 / Accepted: 2 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose A combined in vitro – in silico methodology was designed to estimate pharmacokinetics of budesonide delivered via dry powder inhaler. Methods Particle size distributions from three budesonide DPIs, measured with a Next Generation Impactor and Alberta Idealized Throat, were input into a lung deposition model to predict regional deposition. Subsequent systemic exposure was estimated using a pharmacokinetic model that incorporated Nernst-Brunner dissolution in the conducting airways to predict the net influence of dissolution, mucociliary clearance, and absorption. Results DPIs demonstrated significant in vitro differences in deposition, resulting in large differences in simulated regional deposition in the central conducting airways and the alveolar region. Similar but low deposition in the small conducting airways was observed with each DPI. Pharmacokinetic predictions showed good agreement with in vivo data from the literature. Peak systemic concentration was tied primarily to the alveolar dose, while the area under the curve was more dependent on the total lung dose. Tracheobronchial deposition was poorly correlated with pharmacokinetic data. Conclusions Combination of realistic in vitro experiments, lung deposition modeling, and pharmacokinetic modeling was shown to provide reasonable estimation of in vivo systemic exposure from DPIs. Such combined * Warren H. Finlay [email protected] * Andrew R. Martin [email protected] Conor A. Ruzycki [email protected] 1
Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
approaches are useful in the development of orally inhaled drug products.
KEY WORDS bioequivalence . budesonide dry powder inhalers . in vitro in vivo correlations . lung deposition modeling . pharmacokinetics
ABBREVIATIONS DPI MMAD NGI
Dry powder inhaler Mass median aerodynamic diameter Next Generation Impactor
LIST OF SYMBOLS AUC24 Area under the curve (24 h) FBA Oral bioavailability Fi Fraction of dose depositing in ith compartment Kdiss,TB Effective dissolution rate in tracheobronchial region Pm Measured Pressure Pref Reference Pressure Qpeak Peak inhalation flowrate Tm Measured Temperature Tref Reference Temperature VASL,i Volume of airway surface liquid in ith airway compartment VC Volume of central compartment Vd,ss Volume of distribution at steady state ci Drug concentration in ith airway compartment cmax Maximum serum concentration in central compartment cs Drug solubility dg,50 Particle geometric mean diameter k10 Elimination rate constant k12 Central to peripheral rate constant k21 Peripheral to central rate constant ka Oral absorption rate constant
209
kALV kdiss,ALV kmuc,i kT
Data Loading...
