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

Jens Markus Borghardt, Charlotte Kloft, Ashish Sharma, Jens Markus Borghardt, Charlotte Kloft, Ashish Sharma

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.

Figures

Figure 1
Figure 1
Summary of the lung-specific PK processes for inhaled drugs. Overview of the pulmonary-specific kinetic processes (1–6). The direction of the arrows indicates the direction of each process. For example, drug dissolution is considered to be a unidirectional process.
Figure 2
Figure 2
Schematic overview of the interplay of device and formulation, drug, and patient characteristics. The overlapping areas represent processes or parameters that are influenced or determined by the drug, the formulation/device, or the patient characteristics.
Figure 3
Figure 3
Particle size determines location of drug deposition. Aerodynamic particle size determines deposition patterns across the human respiratory tract. Simulations were performed using Multiple-Path Particle Dosimetry software [95]. Each simulated particle size represents one simulation. The Yeh/Schum five-lobe model [96] with uniform expansion was applied. The inhalation characteristics used for the simulation were an inhaled volume of 2 L, an inhalation flow rate of 60 L/min, and a breath-holding time of 8 seconds. These simulations do not account for the influence of an inhalation device on deposition.
Figure 4
Figure 4
Summary of pulmonary absorption kinetics based on local physiologic characteristics of respiratory tract regions.
Figure 5
Figure 5
Inhaled drug particle deposition in healthy versus diseased lungs. Reproduced with permission from Wang et al. [23].

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