title: Preclinical Experimental and Mathematical Approaches for Assessing Effective Doses of Inhaled Drugs, Using Mometasone to Support Human Dose Predictions.
abstract: 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.
authors: 1 Department of Pharmacology, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Michael
authors: M
authors: Caniga
authors: 4 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Antonio
authors: A
authors: Cabal
authors: 4 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Khamir
authors: K
authors: Mehta
authors: 7 Center for Applied and Computational Mathematics, Rochester Institute of Technology , Rochester, New York.
authors: David S
authors: DS
authors: Ross
authors: 1 Department of Pharmacology, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Malgorzata A
authors: MA
authors: Gil
authors: 1 Department of Pharmacology, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Janice D
authors: JD
authors: Woodhouse
authors: 1 Department of Pharmacology, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Joseph
authors: J
authors: Eckman
authors: 2 Department of Discovery Pharmaceutical Sciences, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: John R
authors: JR
authors: Naber
authors: 2 Department of Discovery Pharmaceutical Sciences, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Marissa K
authors: MK
authors: Callahan
authors: 4 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Luciano
authors: L
authors: Goncalves
authors: 4 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Susan E
authors: SE
authors: Hill
authors: 1 Department of Pharmacology, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Robbie L
authors: RL
authors: Mcleod
authors: 6 Discovery Research Services Charles River Laboratories , Senneville, Quebec, Canada .
authors: Fraser
authors: F
authors: McIntosh
authors: 6 Discovery Research Services Charles River Laboratories , Senneville, Quebec, Canada .
authors: Mark C
authors: MC
authors: Freke
authors: 4 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Sandra A G
authors: SA
authors: Visser
authors: 5 Department of Safety Assessment and Laboratory Animal Sciences, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Neil
authors: N
authors: Johnson
authors: 3 Department of Biology Discovery, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Michael
authors: M
authors: Salmon
authors: 1 Department of Pharmacology, Merck Research Laboratories , Boston, Massachusetts, and West Point, Pennsylvania.
authors: Milenko
authors: M
authors: Cicmil
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000528:Alternaria; D060487:Alternariosis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D054796:Drug Dosage Calculations; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008172:Lung Diseases, Fungal / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D000068656:Mometasone Furoate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D000336:Aerosols; D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D000068656:Mometasone Furoate
keywords: PK/PD modeling; drug dissolution and distribution; inhaled corticosteroid; inhaled delivery; inhaled drug development