Inhaled Therapy in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic Processes

Abstract

The inhalation route is frequently used to administer drugs for the management of respiratory diseases such as asthma or chronic obstructive pulmonary disease. Compared with other routes of administration, inhalation offers a number of advantages in the treatment of these diseases. For example, via inhalation, a drug is directly delivered to the target organ, conferring high pulmonary drug concentrations and low systemic drug concentrations. Therefore, drug inhalation is typically associated with high pulmonary efficacy and minimal systemic side effects. The lung, as a target, represents an organ with a complex structure and multiple pulmonary-specific pharmacokinetic processes, including (1) drug particle/droplet deposition; (2) pulmonary drug dissolution; (3) mucociliary and macrophage clearance; (4) absorption to lung tissue; (5) pulmonary tissue retention and tissue metabolism; and (6) absorptive drug clearance to the systemic perfusion. In this review, we describe these pharmacokinetic processes and explain how they may be influenced by drug-, formulation- and device-, and patient-related factors. Furthermore, we highlight the complex interplay between these processes and describe, using the examples of inhaled albuterol, fluticasone propionate, budesonide, and olodaterol, how various sequential or parallel pulmonary processes should be considered in order to comprehend the pulmonary fate of inhaled drugs.

Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference

“…First, the complexity and limited knowledge of the PK/PD in the lungs, compared to other organs, requires a careful selection of optimal pharmacology tools to ensure accurate assessments. Second, special considerations should be given for products that are delivered via the inhaled route as they have distinct ADME characteristics (Borghardt et al, 2018;Lipworth, 1996;Olsson et al, 2011). Third, different pharmacological assessments are needed depending on whether the drug is a small molecule or a complex therapeutic protein such as a monoclonal antibody (U.S. Food and Drug Administration, 2014).…”

Quality control and testing evaluation of pharmaceutical aerosols

“…Simultaneously, PK studies can be used as a means of explaining the systemic adverse effects that occur systemically, while the aerosols are inhaled through the mouth (Borghardt et al, 2018).…”

“…The widespread availability of sensitive assay methods, such as high-performance liquid chromatography, allows the estimation of plasma and urinary drug levels required for PK evaluation that allows precise and reproducible quantification of drug delivery by determining plasma levels to reflect the effectiveness of lung absorption (Borghardt et al, 2018).…”

“…Clinical studies have demonstrated the precious advantage of inhalation aerosols over systemic therapy for the therapeutic treatment of lung disorders (Borghardt et al, 2018). The inhaled route of administration is chosen to be effective for delivering different types of preventer and reliever drugs to patients with airway obstructions owning the unique advantage of delivering relatively small doses of drug directly to the respiratory tract airways for achieving a high local concentration and diminishing systemic adverse effects; besides they may provide considerable cost savings because of the lower dosage regimens, especially with expensive therapeutic agents.…”

“…The inhaled route of administration is chosen to be effective for delivering different types of preventer and reliever drugs to patients with airway obstructions owning the unique advantage of delivering relatively small doses of drug directly to the respiratory tract airways for achieving a high local concentration and diminishing systemic adverse effects; besides they may provide considerable cost savings because of the lower dosage regimens, especially with expensive therapeutic agents. Consequently, this results in a high therapeutic ratio as compared with other systemic drug delivery either through oral or parenteral route of administration (Borghardt et al, 2018). Numerous and countless studies have shown that the lungs provide substantially superior bioavailability (BA) for macromolecules than any other route of drug delivery to the systemic circulation (Paranjpe and Mü ller-Goymann, 2014;Javadzadeh and Yaqoubi, 2017).…”