Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Abstract

Abstract. During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

Exposure-Response and Clinical Outcome Modeling of Inhaled Budesonide/Formoterol Combination in Asthma Patients

“…Since asthma is a chronic disease which cannot be completely cured, investigation of the PK/PD relationships of these drugs can be important to avoid any unwanted side effects, while achieving the control of asthma that is desired [40,41]. The purpose of the inhaled drugs is to exert their pharmacological activities at the target site, which is the lungs, and the complexity of the pulmonary dissolution and absorption processes have hindered development of PK/PD models for inhaled drugs [42]. PK data is often obtained from plasma concentration levels, and identifying the relationship between plasma PK and the PD effects at the lungs can pose additional challenges [42].…”

“…The purpose of the inhaled drugs is to exert their pharmacological activities at the target site, which is the lungs, and the complexity of the pulmonary dissolution and absorption processes have hindered development of PK/PD models for inhaled drugs [42]. PK data is often obtained from plasma concentration levels, and identifying the relationship between plasma PK and the PD effects at the lungs can pose additional challenges [42]. In this study, the structure of the PK models for both drugs included lung compartments, which were then used to simulate the concentration-time profiles of drugs in the lungs, which had a more reasonable mechanism for their pharmacological effects.…”

Stem cell-based Lung-on-Chips: The best of both worlds?

“…Further, temporal dynamics and patient-specific conditions can be revealed by recapitulating organ-specific barrier functions such as endothelial cell junctions and electrical resistance, presence of specific membrane transporters and metabolic enzymes, genotypic variation, disease conditions, and drug-drug interactions. Also, the effect of elimination processes such as mucociliary clearance on pulmonary bioavailability could be measured [270]. In addition, the flow environment of Organs-on-Chips enables the realistic test of time-dependent effects such as built-up of drug residue or drug carriers that can cause local toxicity [271].…”

A Partial Differential Equation Approach to Inhalation Physiologically Based Pharmacokinetic Modeling

“…To describe the interaction between the lungs and the systemic circulation, it is important to allow for a back-flow of drug from the blood to the lungs. Furthermore, regional differences in surface areas and blood flows are expected to affect the regional rate by which a molecule leaves/enters the lungs, 15 accentuating the spatial heterogeneity in concentrations. Clearly, the sum of these features cannot be well described by unidirectional rate constants for pulmonary absorption rate, such as in refs.…”