Preclinical Experimental and Mathematical Approaches for Assessing Effective Doses of Inhaled Drugs, Using Mometasone to Support Human Dose Predictions

Understanding the relationship between dose, lung exposure, and drug efficacy continues to be a challenging aspect of inhaled drug development. An experimental inhalation platform was developed using mometasone furoate to link rodent lung exposure to its in vivo pharmacodynamic (PD) effects. We asse...

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Bibliographic Details
Published in:	Journal of aerosol medicine and pulmonary drug delivery Vol. 29; no. 4; p. 362
Main Authors:	Caniga, Michael, Cabal, Antonio, Mehta, Khamir, Ross, David S, Gil, Malgorzata A, Woodhouse, Janice D, Eckman, Joseph, Naber, John R, Callahan, Marissa K, Goncalves, Luciano, Hill, Susan E, Mcleod, Robbie L, McIntosh, Fraser, Freke, Mark C, Visser, Sandra A G, Johnson, Neil, Salmon, Michael, Cicmil, Milenko
Format:	Journal Article
Language:	English
Published:	United States 01-08-2016
Subjects:	Administration, Inhalation Aerosols Alternaria Alternariosis - drug therapy Alternariosis - metabolism Alternariosis - microbiology Alternariosis - physiopathology Animals Anti-Inflammatory Agents - administration & dosage Anti-Inflammatory Agents - pharmacokinetics Disease Models, Animal Drug Dosage Calculations Humans Lipopolysaccharides Lung - drug effects Lung - metabolism Lung - physiopathology Lung Diseases, Fungal - drug therapy Lung Diseases, Fungal - metabolism Lung Diseases, Fungal - microbiology Lung Diseases, Fungal - physiopathology Male Models, Biological Mometasone Furoate - administration & dosage Mometasone Furoate - pharmacokinetics Pneumonia - chemically induced Pneumonia - drug therapy Pneumonia - metabolism Pneumonia - physiopathology Rats, Inbred BN Rats, Sprague-Dawley Species Specificity Tissue Distribution PK/PD modeling inhaled drug development inhaled delivery drug dissolution and distribution inhaled corticosteroid
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Summary:	Understanding the relationship between dose, lung exposure, and drug efficacy continues to be a challenging aspect of inhaled drug development. An experimental inhalation platform was developed using mometasone furoate to link rodent lung exposure to its in vivo pharmacodynamic (PD) effects. We assessed the effect of mometasone delivered directly to the lung in two different rodent PD models of lung inflammation. The data obtained were used to develop and evaluate a mathematical model to estimate drug dissolution, transport, distribution, and efficacy, following inhaled delivery in rodents and humans. Mometasone directly delivered to the lung, in both LPS and Alternaria alternata rat models, resulted in dose dependent inhibition of BALf cellular inflammation. The parameters for our mathematical model were calibrated to describe the observed lung and systemic exposure profiles of mometasone in humans and in animal models. We found that physicochemical properties, such as lung fluid solubility and lipophilicity, strongly influenced compound distribution and lung retention. Presently, we report on a novel and sophisticated mathematical model leading to improvements in a current inhaled drug development practices by providing a quantitative understanding of the relationship between PD effects and drug concentration in lungs.
ISSN:	1941-2703
DOI:	10.1089/jamp.2015.1253