Pharmacokinetic/pharmacodynamic approaches to drug delivery design for inhalation drugs

ABSTRACT

Introduction: Inhaled drugs are important in the treatment of many lung pathologies, but to be therapeutically effective they must reach unbound concentrations at their effect site in the lung that are adequate to interact with their pharmacodynamic properties (PD) and exert the pharmacological action over an appropriate dosing interval. Therefore, the evaluation of pharmacokinetic (PK)/PD relationship is critical to predict their possible therapeutic effect.

Areas covered: We review the approaches used to assess the PK/PD relationship of the major classes of inhaled drugs that are prescribed to treat pulmonary pathologies.

Expert opinion: There are still great difficulties in producing data on lung concentrations of inhaled drugs and interpreting them as to their ability to induce the desired therapeutic action. The structural complexity of the lungs, the multiplicity of processes involved simultaneously and the physical interactions between the lungs and drug make any PK/PD approach to drug delivery design for inhalation medications extremely challenging. New approaches/methods are increasing our understanding about what happens to inhaled drugs, but they are still not ready for regulatory purposes. Therefore, we must still rely on plasma concentrations based on the axiom that they reflect both the extent and the pattern of deposition within the lungs.

KEYWORDS:

• Inhalation route
• inhalers
• pharmacodynamics
• pharmacokinetics
• PK/PD approaches

Article highlights

• Evaluating the relationship between drug concentration (PK) and its pharmacological effect (PD) is fundamental to predicting the time course of clinical outcomes resulting from a certain dosing regimen and provide a more rational basis for patient specific individualized dosing.

• The inhalation route offers a number of advantages over systemic routes of drug administration when lung diseases must be treated.

• There are still great difficulties in producing data on lung concentrations of inhaled drugs and, above all, in interpreting them with regard to their ability to induce the desired therapeutic action.

• The complexity of the pulmonary disposition of inhaled drugs caused by the multiplicity of processes involved at the same time and the structural complexity of the lungs makes any PK/PD approach to drug delivery design for inhalation drugs extremely difficult.

• Until we can determine the temporal unbound concentrations of the inhaled drug in the pulmonary site of action, we will have to rely on plasma concentrations, based on the axiom that the unbound drug concentration at the level of the subepithelial smooth muscle can be assumed to be the same as that measured in blood plasma.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has declared that they are co-founder and scientific expert for Cynbiose Respiratory. In the past 3 years, she received consultancy fees from Argenx, Eli Lilly and research support from Signia Therapeutics, Sanofi and Aerogen Ltd. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.