Pulmonary Drug Metabolism, Clearance, and Absorption

Olsson, Bo; Bondesson, Eva; Borgström, Lars; Edsbäcker, Staffan; Eirefelt, Stefan; Ekelund, Katarina; Gustavsson, Lena; Hegelund-Myrbäck, Tove

doi:10.1007/978-1-4419-9745-6_2

Cited by 114 publications

(90 citation statements)

References 149 publications

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“…Qualitatively and quantitatively, different compositions and volumes of the alveolar and the conducting airway lining fluids, as well as a thin fluid layer in the alveolar space (and in the peripheral conducting airways of the lung) might reason different dissolution characteristics dependent on where drug particles are deposited. However, it remains to be elucidated whether drug dissolution is faster in the peripheal or the central parts of the lung (13). Up to date quantitative characterization of the in vivo interplay of all contributing factors either with in vitro assays or with in silico methods is difficult.…”

Section: Pulmonary Drug Dissolutionmentioning

confidence: 99%

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Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Borghardt

Weber

Staab

et al. 2015

AAPS J

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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.

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Section: Pulmonary Drug Dissolutionmentioning

confidence: 99%

“…Especially for lipophilic drugs, pulmonary dissolution can represent the rate-limiting process and systemic exposure after drug inhalation is discussed to depend on the pulmonary drug dissolution characteristics (see below). A book chapter by Olsson et al provides an excellent overview on pulmonary dissolution processes (13).…”

Section: Pulmonary Drug Dissolutionmentioning

confidence: 99%

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Borghardt

Weber

Staab

et al. 2015

AAPS J

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“…However, for particles having sizes greater than 6-10 µm or below 0.2 µm, and/or with a hydrophilic particle surface (e.g., PEG molecules), phagocytosis seems to be prevented or reduced [33][34][35]. Consequently, according to their dissolution velocity, deposited drug particles can be progressively eliminated by these mechanisms or dissolved to act on their pharmacological target and/or be metabolised or absorbed through lung epithelium [36][37]. Indeed, lipophilic drugs pass easily through the cell membranes of the lung epithelium by passive diffusion (i.e., transcellular transport).…”

Section: Pulmonary Drug Deliverymentioning

confidence: 99%

Recent Developments in Inhaled Triazoles Against Invasive Pulmonary Aspergillosis

Merlos

Amighi

Wauthoz

2014

Curr Fungal Infect Rep

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Invasive pulmonary aspergillosis (IPA) presents high incidence and high mortality in immunocompromised patients. To combat or prevent IPA, triazoles such as voriconazole or itraconazole and posaconazole are becoming the first-or second-line therapy, respectively.However, triazoles present issues of oral bioavailability, high liver metabolism and/or drugdrug interactions, increasing the variability of systemic concentrations. To overcome these issues, inhalation is a promising route for delivering triazoles for prophylactic or curative therapy of IPA. Indeed, pulmonary drug delivery increases the drug in situ drastically while decreasing the systemic exposure, therefore limiting drug metabolisation, side effects and drug-drug interactions. Development of triazoles for inhalation has focused on voriconazole and itraconazole, drugs which are both highly permeable but present high solubility differences. In this review, the most complete and promising pharmaceutical developments for voriconazole and itraconazole are described.Keywords: aerosol, antifungal, aspergillosis, fungal infection, pulmonary delivery, dry powder inhaler, dry powder for inhalation, nebulizer, nebulization, cyclodextrin, nanoparticle, solid dispersion, controlled release drug delivery. Abbreviations: AI90H, amorphous itraconazole with Phospholipon

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“…Respiratory diseases are preferably treated with inhaled drugs because pulmonary drug delivery can provide a rapid onset of action and an improved therapeutic index owing to lung selective drug exposure (Olsson et al, 2011). However, PK/PD relationships are not easily established for locally acting inhaled drugs because the drug concentration in blood cannot be assumed to reflect the target site concentration in lung tissue (Cooper et al, 2012), and furthermore, there are no established methodologies to assess this concentration.…”

Section: Introductionmentioning

confidence: 99%

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

Boger

Ewing

Eriksson

et al. 2015

J Pharmacol Exp Ther

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Investigation of pharmacokinetic/pharmacodynamic (PK/PD) relationships for inhaled drugs is challenging because of the limited possibilities of measuring tissue exposure and target engagement in the lung. The aim of this study was to develop a methodology for measuring receptor occupancy in vivo in the rat for the glucocorticoid receptor (GR) to allow more informative inhalation PK/PD studies. From AstraZeneca's chemical library ofpropoxy]indazol-1-yl]-N-methyl-benzamide] was identified to have properties that are useful as a tracer for GR in vitro. When given at an appropriate dose (30 nmol/kg) to rats, compound 1 functioned as a tracer in the lung and spleen in vivo using liquid chromatography-tandem mass spectrometry bioanalysis. The methodology was successfully used to show the dose-receptor occupancy relationship measured at 1.5 hours after intravenous administration of fluticasone propionate (20, 150, and 750 nmol/kg) as well as to characterize the time profile for receptor occupancy after a dose of 90 nmol/kg i.v. The dose giving 50% occupancy was estimated as 47 nmol/kg. The methodology is novel in terms of measuring occupancy strictly in vivo and by using an unlabeled tracer. This feature confers key advantages, including occupancy estimation not being influenced by drug particle dissolution or binding/dissociation taking place postmortem. In addition, the tracer may be labeled for use in positron emission tomography imaging, thus enabling occupancy estimation in humans as a translatable biomarker of target engagement.

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Pulmonary Drug Metabolism, Clearance, and Absorption

Cited by 114 publications

References 149 publications

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Recent Developments in Inhaled Triazoles Against Invasive Pulmonary Aspergillosis

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

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