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© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
J. Lam, P. C. L. Kwok (eds.), RespiratoryDeliveryofBiologics,NucleicAcids,and
Vaccines, AAPS Introductions in the Pharmaceutical Sciences 8
https://doi.org/10.1007/978-3-031-47567-2_9
PharmacokineticsofInhaled
Medications–WhatDoWeKnowAbou t
BiologicalMacromolecules?
Audrey Huili Lim
1, 2
, Jinxin Zhao
1, 3
, Nusaibah Abdul Rahim
1, 2
,
Jing Zhao4, Haiting Liu4, Xiaoyan Yang4 and Yu-Wei Lin
1, 2, 3
Malaya Translational and Clinical Pharmacometrics Group, Faculty
of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia
Department of Clinical Pharmacy and Pharmacy Practice, Faculty
of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia
Infection Program and Department of Microbiology, Monash
Biomedicine Discovery Institute, Monash University, Melbourne,
VIC, Australia
Department of Neonatology, West China Second University
Hospital of Sichuan University, Chengdu, Sichuan, People’s
Republic of China
Yu-WeiLin
Email:yuwei.lin@um.edu.my
Abstract
Over the last decades, biological macromolecules have attracted
growing attention and have become an important therapeutic
modality. Biological macromolecules are peptide- and protein-based
therapeutics with unique pharmacokinetic (PK) and
pharmacodynamic (PD) properties. Due to its poor bioavailability,
biological macromolecules are usually administered via the parenteral
route. Pulmonary administration of biological macromolecules is
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increasingly employed for treating various diseases, including
respiratory viral infections. Due to its complex PK/PD, clinical
development of inhaled biological macromolecules remains
challenging. In this context, pharmacometrics using quantitative
modeling and simulation techniques offer critical insight in
understanding the complex PK/PD and providing guidance at various
stages throughout the development of inhaled biological
macromolecules. This chapter provides an overview of the key
pulmonary PK processes and the available modeling and simulation
(M&S) tools that can be used to assess and understand PK in the
clinical development of inhaled medications, including biological
macromolecules.
Keywords Biologics – Mathematical model – Model-informed drug
development – Pharmacokinetics – Pharmacometrics
1 Introd uction
Respiratory diseases represent a major global health burden, with
approximately 70,000 people living with cystic ibrosis, 250 million
with chronic obstructive pulmonary disease (COPD), and 20 million
with asthma [1–3]. Furthermore, the annual global death toll from lung
cancers and/or pneumonia represents the single largest death,
accounting for more than 1.8 million deaths annually [4]. This igure is
expected to rise sharply due to the recent outbreak of the COVID-19
pandemic. The respiratory drug market is growing at a rate of 4–6%
annually; many new therapeutics, including biologics, are currently
under development [5].
Biologics refers to a diverse group of large and complex molecules
manufactured in, extracted from, or semi-synthesized from biological
sources [6]. Generally, biopharmaceuticals range from vaccines and
growth factors to enzymes, fusion proteins, hormones, and monoclonal
antibodies. Biologics have high commercial potential as they are often
associated with high speciicity and high target binding afinity.
Nonetheless, biologics are also associated with several limitations, for
example, fragility, risk of immune response, high cost, and often
require speciic storage conditions to prevent degradation [6–9].
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Biological macromolecules including therapeutic peptides, proteins,
and antibodies, represent the largest group of biological drugs and are
the focus of this chapter.
Successful delivery of biological macromolecules via a non-invasive
route remains elusive due to their high polarity and large molecular
size [6]. Various non-invasive routes of administration have been
investigated for the delivery of biological macromolecules such as oral,
nasal, inhalation, and transdermal routes. Pulmonary administration is
an attractive route because of the large surface area, extensive
vascularization, and high tissue permeability, which enable rapid
absorption (depending on the modality) and the potential for rapid
onset of activity if the target is local. Moreover, the inhaled route is a
comparatively easier form of administration and allows potential selfadministration by patients [10]. Pulmonary delivery also offers the
advantage of achieving high concentrations in the lungs. To achieve the
same drug concentrations in the lungs after systemic drug
administration, higher doses would normally be needed compared
with inhalation, which would be associated with an increased risk of
side effects [11, 12]. As such, aerosolized biological macromolecules
are preferable for the treatment of lung diseases such as asthma, lung
infection, and COPD [6]. In addition, there is little irst-pass metabolism
and proteolytic enzyme activity in the lungs [11, 13].
Clinical pharmacology is the study of the interactions between
drugs and the human body and comprises two broad divisions:
pharmacokinetics (PK) and pharmacodynamics (PD) [14]. PK is
deined as the study of the time course of drug absorption,
distribution, metabolism, and elimination (i.e., ADME) while PD is
deined as the relationship between drug concentration and the
resulting therapeutic effect [15]. Simplistically, PK is the study of what
the body does to the drug, whereas PD is the study of what the drug
does to the body. Characterization of the relationship between PK and
PD is imperative in the discovery and development of new molecules in
the pharmaceutical industry. Insights from PK and PD analyses are
used by researchers to design better clinical studies, and by clinicians
to advise treatment options [16, 17]. The role of mathematical
modeling to assess and understand the deposition, PK, and PD of
inhaled drugs has gained signiicant interest over the last decade [18].
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This chapter provides an overview of the key pulmonary PK processes
and the available modeling and simulation (M&S) tools that can be
used to assess and understand PK in the clinical development of
inhaled medication, including biological macromolecules.
2 KeyDeterminantsofPulmonaryPK
To understand PK following inhalation, a thorough understanding of
the key kinetic processes is crucial (Table 1 and Fig. 1). It should be
noted that the key factors governing the PK of inhaled biological
macromolecules are currently not fully understood. Our current
understanding of the PK of inhaled biological molecules is very limited
and available literature is mostly based on nonclinical models with
very limited clinical utility. This section provides an overview of the
key factors impacting pulmonary PK processes based on our
understanding of small molecules. It is expected that these factors are
also applicable to inhaled biological macromolecules.
Table1 Key determinants that affect pulmonary and systemic PK following
inhalation
Kinetic
process
Keydeterminants
Pulmonary
deposition
Lung morphology, inhalation techniques, formulation, aerosol
velocity, geometry, particle size and particle density
Pulmonary
dissolution
Physiochemical property of the drug/formulation (e.g., solubility)
and the physiology of the lungs
Absorption Bronchial mucus layer, alveolar surfactant, lung epithelium,
lipophilicity, the degree of ionization, molecular weight, drug
transporters, areas of the lungs
Distribution Degree of ionization, lipophilicity
Metabolism Expression levels and patterns of the metabolic enzymes, lung
macrophages
Elimination Particle size, solubility, deposition site
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Fig.1 Schematic representation of the kinetic processes following inhalation.
(Adapted from Borghart et al. [18]). Light purple boxes = particle/droplet deposition
compartments; light orange boxes = absorption compartments; purple
boxes = blood/plasma compartments; purple area = processes associated with
pulmonary; blue area = processes associated with the systemic PK
2.1 PulmonaryPhysiology
The lungs are a pair of complex, heterogeneous, pyramid-shaped
organs situated in the thoracic cavity (Fig. 2). They are the
foundational organs of the respiratory system and consist of two main
functional areas: gas exchange parenchyma (e.g., alveolar sacs) and
conducting airways (e.g., bronchioles) [19–21].
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Fig.2 Lung physiology. (Adapted from Williams [22])
Conducting airways bifurcate approximately 17 times, getting
smaller with each sequential bifurcation [23–25]. The airways are lined
with pseudo-stratiied columnar epithelia, which are mostly composed
of basal cells, secretory cells (e.g., goblet and serous cells), and ciliated
cells [24, 25]. The walls of conducting airways are too thick for
diffusion, and this region does not contain alveoli to facilitate oxygencarbon dioxide exchange. The main functions of the conducting
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