Pulmonary absorption – estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis

Eriksson, Johanna; Sjögren, Erik; Thörn, Helena; Rubin, Katarina; Bäckman, Per; Lennernäs, Hans

doi:10.1016/j.ejpb.2017.11.013

Cited by 37 publications

(37 citation statements)

References 48 publications

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“…The isolated perfused rat lung (IPL) model is an ex vivo absorption model that allows parameters like epithelial permeability, solubility in epithelial lining fluid (ELF), dissolution rate, and particle wetting as well as tissue retention to be determined by computational analysis (4,5). The advantages of the IPL model over in vivo inhalation studies is that the lung-delivered dose can be closely controlled without passing the nose and the lung deposited dose can be measured directly by mass balance calculations (6,7).…”

Section: Introductionmentioning

confidence: 99%

Drug Absorption Parameters Obtained Using the Isolated Perfused Rat Lung Model Are Predictive of Rat In Vivo Lung Absorption

Eriksson

Sjögren

Lennernäs

et al. 2020

AAPS J

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The ex vivo isolated perfused rat lung (IPL) model has been demonstrated to be a useful tool during drug development for studying pulmonary drug absorption. This study aims to investigate the potential use of IPL data to predict rat in vivo lung absorption. Absorption parameters determined from IPL data (ex vivo input parameters) in combination with intravenously determined pharmacokinetic data were used in a biopharmaceutics model to predict experimental rat in vivo plasma concentration-time profiles and lung amount after inhalation of five different inhalation compounds. The performance of simulations using ex vivo input parameters was compared with simulations using in vitro input parameters, to determine whether and to what extent predictability could be improved by using input parameters determined from the more complex ex vivo model. Simulations using ex vivo input parameters were within twofold average difference (AAFE < 2) from experimental in vivo data for all compounds except one. Furthermore, simulations using ex vivo input parameters performed significantly better than simulations using in vitro input parameters in predicting in vivo lung absorption. It could therefore be advantageous to base predictions of drug performance on IPL data rather than on in vitro data during drug development to increase mechanistic understanding of pulmonary drug absorption and to better understand how different substance properties and formulations might affect in vivo behavior of inhalation compounds.

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Section: Introductionmentioning

confidence: 99%

Drug Absorption Parameters Obtained Using the Isolated Perfused Rat Lung Model Are Predictive of Rat In Vivo Lung Absorption

Eriksson

Sjögren

Lennernäs

et al. 2020

AAPS J

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“…Typically derived of rodent or rabbit origin which differs in tracheobronchial anatomical and structural composition when compared to human lungs. Hochhaus et al, 1997;Beck-Broichsitter et al, 2009;Eriksson et al, 2018 efficacy in the heart and relieve pulmonary hypertension (Paranjpe et al, 2013). The use of ex vivo PCLS models to determine in vivo toxicities and therapeutic efficacies are a clinically relevant, prevalidation research platform.…”

Section: Precision-cut Lung Slices Maintainmentioning

confidence: 99%

“…IPL models are used to determine the uptake of inhaled agents across the pulmonary epithelium, the subsequent rate of drug absorption and therapeutic efficacy (Hochhaus et al, 1997;Bosquillon et al, 2017;Eriksson et al, 2018). IPL has been used to explore the drug transport profiles of inhaled (ventilated)/nebulized compounds, or nanoparticles, that have been formulated to achieve deposition in the tracheal, bronchial or alveolar lung regions with high drug permeability, absorption and retention (Tronde et al, 2002;Ewing et al, 2006;Beck-Broichsitter et al, 2009;Selg et al, 2013;Eriksson et al, 2020).…”

Section: Isolated Perfused Lungs Are a Unique Platform To Determine Imentioning

confidence: 99%

Modifying and Integrating in vitro and ex vivo Respiratory Models for Inhalation Drug Screening

Cidem

Bradbury

Traini

et al. 2020

Front. Bioeng. Biotechnol.

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“…Optimal pulmonary drug delivery for locally acting drugs includes a high local lung concentration, extended lung residence time and low systemic concentration [88]. A fundamental understanding of pulmonary dissolution, residence time, and lung absorption processes is key for the successful development of inhaled products [89,90]. However, inhaled formulations have many challenges, including formulation stability, pulmonary distribution, lung toxicity, and additives safety [91].…”

Section: Prediction Of Human Pharmacokineticsmentioning

confidence: 99%

Model-Informed Drug Discovery and Development Strategy for the Rapid Development of Anti-Tuberculosis Drug Combinations

et al. 2020

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The increasing emergence of drug-resistant tuberculosis requires new effective and safe drug regimens. However, drug discovery and development are challenging, lengthy and costly. The framework of model-informed drug discovery and development (MID3) is proposed to be applied throughout the preclinical to clinical phases to provide an informative prediction of drug exposure and efficacy in humans in order to select novel anti-tuberculosis drug combinations. The MID3 includes pharmacokinetic-pharmacodynamic and quantitative systems pharmacology models, machine learning and artificial intelligence, which integrates all the available knowledge related to disease and the compounds. A translational in vitro-in vivo link throughout modeling and simulation is crucial to optimize the selection of regimens with the highest probability of receiving approval from regulatory authorities. In vitro-in vivo correlation (IVIVC) and physiologically-based pharmacokinetic modeling provide powerful tools to predict pharmacokinetic drug-drug interactions based on preclinical information. Mechanistic or semi-mechanistic pharmacokinetic-pharmacodynamic models have been successfully applied to predict the clinical exposure-response profile for anti-tuberculosis drugs using preclinical data. Potential pharmacodynamic drug-drug interactions can be predicted from in vitro data through IVIVC and pharmacokinetic-pharmacodynamic modeling accounting for translational factors. It is essential for academic and industrial drug developers to collaborate across disciplines to realize the huge potential of MID3.

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Pulmonary absorption – estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis

Cited by 37 publications

References 48 publications

Drug Absorption Parameters Obtained Using the Isolated Perfused Rat Lung Model Are Predictive of Rat In Vivo Lung Absorption

Drug Absorption Parameters Obtained Using the Isolated Perfused Rat Lung Model Are Predictive of Rat In Vivo Lung Absorption

Modifying and Integrating in vitro and ex vivo Respiratory Models for Inhalation Drug Screening

Model-Informed Drug Discovery and Development Strategy for the Rapid Development of Anti-Tuberculosis Drug Combinations

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