Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Accurately Predicts the Better Bronchodilatory Effect of Inhaled Versus Oral Salbutamol Dosage Forms

Boger, Elin; Fridén, Markus

doi:10.1089/jamp.2017.1436

Cited by 36 publications

(22 citation statements)

References 45 publications

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“…(27) Most importantly, functional readouts are required to define the free (active) drug at relevant pharmacological target sites as target engagement will not be possible unless we have free compound in solution ready to interact with target receptor. The data on distribution and retention of salbutamol are consistent with a recently published PBPK paper by Boger and Fridén (28) on predicted free concentration of salbutamol after oral and inhaled administration. The model predicted that inhalation will lead to spatial heterogeneity in the target site concentrations with highest free drug concentration in the epithelium and subepithelium.…”

Section: Discussionsupporting

confidence: 89%

Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging

Hamm

Bäckström

Brülls

et al. 2020

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: For the treatment of respiratory disease, inhaled drug delivery aims to provide direct access to pharmacological target sites while minimizing systemic exposure. Despite this long-held tenet of inhaled therapeutic advantage, there are limited data of regional drug localization in the lungs after inhalation. The aim of this study was to investigate the distribution and retention of different chemotypes typifying available inhaled drugs [slowly dissolving neutral fluticasone propionate (FP) and soluble bases salmeterol and salbutamol] using mass spectrometry imaging (MSI). Methods: Salmeterol, salbutamol, and FP were simultaneously delivered by inhaled nebulization to rats. In the same animals, salmeterol-d 3 , salbutamol-d 3 , and FP-d 3 were delivered by intravenous (IV) injection. Samples of lung tissue were obtained at 2-and 30-minute postdosing, and high-resolution MSI was used to study drug distribution and retention. Results: IV delivery resulted in homogeneous lung distribution for all molecules. In comparison, while inhalation also gave rise to drug presence in the entire lung, there were regional chemotype-dependent areas of higher abundance. At the 30-minute time point, inhaled salmeterol and salbutamol were preferentially retained in bronchiolar tissue, whereas FP was retained in all regions of the lungs. Conclusion: This study clearly demonstrates that inhaled small molecule chemotypes are differentially distributed in lung tissue after inhalation, and that high-resolution MSI can be applied to study these retention patterns.

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Section: Discussionsupporting

confidence: 89%

Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging

Hamm

Bäckström

Brülls

et al. 2020

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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“…These results provide a quantification of lung targeting for salbutamol after inhalation, which can be expected to translate to a therapeutic advantage of the inhaled dosage form. This therapeutic advantage will decrease as moving from central towards peripheral lung and from ELF towards blood through lung tissue as was recently described by PK/PD modelling (Boger & Fridén, 2019). This targeting is assumed to be primarily driven by the low permeability of salbutamol, which results in retention of the compound inside cells.…”

Section: Discussionmentioning

confidence: 91%

Lung pharmacokinetics of inhaled and systemic drugs: A clinical evaluation

Sadiq

Holz

Ellinghusen

et al. 2021

British J Pharmacology

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United Kingdom) for scientific exchange and technical advice. We thank the clinical study volunteers for their participation and the site staff for their diligent study conduct. We also thank Richard Claes, PhD, of PharmaGenesis London (London, United Kingdom) for providing medical writing support, which was funded by AstraZeneca (Gothenburg, Sweden) in accordance with Good Publication Practice 3 (GPP3) guidelines (http://www.ismpp.org/gpp3).

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“…To our knowledge, this is the first time that tracheal blood flow in rats has been estimated separately from the bronchial blood flow. Boger et al [42] implemented generation-specific blood flow in their physiologically-based PK model as a function of airway diameter, based on an equation evaluated with dog data [43]. This relationship has not yet been validated for rats.…”

Section: Discussionmentioning

confidence: 99%

Towards a Quantitative Mechanistic Understanding of Localized Pulmonary Tissue Retention—A Combined In Vivo/In Silico Approach Based on Four Model Drugs

et al. 2020

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Increasing affinity to lung tissue is an important strategy to achieve pulmonary retention and to prolong the duration of effect in the lung. As the lung is a very heterogeneous organ, differences in structure and blood flow may influence local pulmonary disposition. Here, a novel lung preparation technique was employed to investigate regional lung distribution of four drugs (salmeterol, fluticasone propionate, linezolid, and indomethacin) after intravenous administration in rats. A semi-mechanistic model was used to describe the observed drug concentrations in the trachea, bronchi, and the alveolar parenchyma based on tissue specific affinities (Kp) and blood flows. The model-based analysis was able to explain the pulmonary pharmacokinetics (PK) of the two neutral and one basic model drugs, suggesting up to six-fold differences in Kp between trachea and alveolar parenchyma for salmeterol. Applying the same principles, it was not possible to predict the pulmonary PK of indomethacin, indicating that acidic drugs might show different pulmonary PK characteristics. The separate estimates for local Kp, tracheal and bronchial blood flow were reported for the first time. This work highlights the importance of lung physiology- and drug-specific parameters for regional pulmonary tissue retention. Its understanding is key to optimize inhaled drugs for lung diseases.

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Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Accurately Predicts the Better Bronchodilatory Effect of Inhaled Versus Oral Salbutamol Dosage Forms

Cited by 36 publications

References 45 publications

Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging

Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging

Lung pharmacokinetics of inhaled and systemic drugs: A clinical evaluation

Towards a Quantitative Mechanistic Understanding of Localized Pulmonary Tissue Retention—A Combined In Vivo/In Silico Approach Based on Four Model Drugs

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