Anneke Himstedt (1,2), Sebastian Georg Wicha (1), Jens Markus Borghardt (2)
(1) Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany (2) Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
Introduction: Since development and production of orally inhaled drug products is challenging [1], oral inhalation is often only considered if oral administration is not feasible due to systemic adverse effects. In comparison to systemic administration, pulmonary selectivity after drug inhalation allows lowering the administered dose, which is expected to reduce systemic adverse effects to a potentially relevant extent. The magnitude of required pulmonary selectivity is however rarely investigated prior to any research activities.
Objective: A modelling and simulation approach was employed to evaluate the pulmonary selectivity of the three model drugs fluticasone propionate (FP), budesonide (BUD) and salmeterol (SAL). The objective was to investigate the impact on the pulmonary selectivity by (i) the route of administration (intravenous, oral, and oral inhalation), and (ii) the lung region (conducting airways or peripheral lung). The developed model was further used to perform a sensitivity analyses to identify potential optimization parameters for orally inhaled drug products to achieve higher pulmonary selectivity.
Methods: All analyses were performed in R (version 3.3.2) [2, 3]. A compartmental model accounting for simple deposition patterns (central and peripheral), dissolution, mucocilary clearance, as well as absorption from the conducting airways, the alveolar space and the gastro intestinal tract was parameterized based on literature information [4-22] and in-house data. A bi-directional flow was considered between the central compartment and the lung compartments.
Simulations of unbound concentration-time profiles in plasma, conducting airways and alveolar space were performed for the three different routes of administration. Pulmonary selectivity for both lung regions was defined as either the ratio (pulmonary/systemic) of the area under the unbound concentration-time curves (AUCfree) or trough concentrations (Cmin,free). The sensitivity of pulmonary selectivity was evaluated by increasing and decreasing each model parameter by two-fold.
Results: Only oral inhalation was predicted to provide pulmonary selectivity in any lung region (AUC-based selectivity > 1.0). While all drugs showed selectivity in the conducting airways after oral inhalation, only FP showed slightly increased selectivity in the alveolar region (AUC-based selectivity: 1.21). The sensitivity analysis suggested the pulmonary blood flow, the systemic clearance and the deposition patterns as the most important determinants of AUC-based selectivity in the conducting airways. The mucociliary clearance and the dissolution rate influenced the pulmonary selectivity of FP, and pulmonary selectivity of both SAL and BUD was sensitive to the lung dose and oral bioavailability. Tissue affinity did not influence the AUC-based pulmonary selectivity, but had an effect on the selectivity at Cmin.
Conclusions: Modelling and simulation allow an early assessment of the pulmonary selectivity provided by oral inhalation. In contrast to oral inhalation, neither oral nor intravenous administration showed any pulmonary PK selectivity in either lung region. While pulmonary drug delivery did show an advantage over other routes of administration for targets located in the conducting airways, no clear advantage could be shown for targets in the alveolar region. According to the sensitivity analysis, the main optimization parameters of orally inhaled drug products are the pulmonary deposition pattern, pulmonary tissue affinity, and the systemic clearance.
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Reference: PAGE () Abstr 9526 [www.page-meeting.org/?abstract=9526]
Poster: Drug/Disease Modelling - Absorption & PBPK