Michael Caniga1, Antonio Cabal2, Khamir Mehta2, David S Ross3, Malgorzata A Gil1, Janice D Woodhouse1, Joseph Eckman1, John R Naber4, Marissa K Callahan4, Luciano Goncalves2, Susan E Hill2, Robbie L Mcleod1, Fraser McIntosh5, Mark C Freke5, Sandra A G Visser2, Neil Johnson6, Michael Salmon7, Milenko Cicmil1. 1. 1 Department of Pharmacology, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania. 2. 4 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania. 3. 7 Center for Applied and Computational Mathematics, Rochester Institute of Technology , Rochester, New York. 4. 2 Department of Discovery Pharmaceutical Sciences, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania. 5. 6 Discovery Research Services Charles River Laboratories , Senneville, Quebec, Canada . 6. 5 Department of Safety Assessment and Laboratory Animal Sciences, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania. 7. 3 Department of Biology Discovery, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS:Mometasone directly delivered to the lung, in both LPS and Alternaria alternatarat 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. CONCLUSIONS: 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.
Entities:
Keywords:
PK/PD modeling; drug dissolution and distribution; inhaled corticosteroid; inhaled delivery; inhaled drug development
Authors: Per Bäckman; Antonio Cabal; Andy Clark; Carsten Ehrhardt; Ben Forbes; Jayne Hastedt; Anthony Hickey; Guenther Hochhaus; Wenlei Jiang; Stavros Kassinos; Philip J Kuehl; David Prime; Yoen-Ju Son; Simon P Teague; Ulrika Tehler; Jennifer Wylie Journal: Mol Pharm Date: 2022-05-24 Impact factor: 5.364