Prediction of Efficacious Inhalation Lung Doses via the Use of In Silico Lung Retention Quantitative Structure-Activity Relationship Models and In Vitro Potency Screens

Lung concentrations of a drug are expected to drive the pharmacodynamic response to local inflammation after inhalation delivery, and the only way of determining the efficacious dose has been to measure it directly in animal models. In this study, we present a method to predict efficacious lung doses after inhalation in a rat lipopolysaccharide challenge model from in silico predictions of lung concentration and in vitro measurements only. A quantitative structure-activity relationship (QSAR) model, based on calculated physical properties predicted the partitioning of 34 compounds between lung and plasma. Because it was observed that lung/plasma partitioning correlated with lung concentration, it was possible to use this relationship to predict lung concentration at a given dose and time point. Based on the pharmacokinetic-pharmacodynamic (PKPD) relationship observed, a minimal free lung concentration relative to potency to drive significant inhibition of neutrophilia was established. By using predicted lung concentrations, measured fraction unbound in plasma, and cellular potency, it was possible to estimate an inhaled lung dose that would be expected to achieve this target exposure. These predictions were made for 23 compounds, which were not part of the original QSAR training set, and all except one were predicted to within 3-fold of their measured values. This novel approach shows that by understanding PKPD relationships and drivers for lung affinity after inhalation dosing, it is possible to estimate in vivo lung doses required for efficacy. This methodology provides a useful screening tool to rank candidate compounds and minimizes the use of extensive animal testing.

[1]  L S Schanker,et al.  Absorption of aerosolized drugs from the rat lung. , 1983, Drug metabolism and disposition: the biological fate of chemicals.

[2]  S. Wold,et al.  Multi‐way principal components‐and PLS‐analysis , 1987 .

[3]  M. Dahlbäck,et al.  A novel dry powder aerosol delivery system for real time measurement of the inhaled dose to large animals (dogs) , 1997 .

[4]  K. Pinkerton,et al.  Site-selective differences in cytochrome P450 isoform activities. Comparison of expression in rat and rhesus monkey lung and induction in rats. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[5]  Yilin Wang,et al.  QSPR Studies on Vapor Pressure, Aqueous Solubility, and the Prediction of Water-Air Partition Coefficients , 1998, J. Chem. Inf. Comput. Sci..

[6]  O. Hankinson,et al.  CYP1A1 levels in lung tissue of tobacco smokers and polymorphisms of CYP1A1 and aromatic hydrocarbon receptor. , 2001, Pharmacogenetics.

[7]  C. Johansson,et al.  Pharmacokinetics of budesonide and its major ester metabolite after inhalation and intravenous administration of budesonide in the rat. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[8]  Pierre Bruneau,et al.  Search for Predictive Generic Model of Aqueous Solubility Using Bayesian Neural Nets , 2001, J. Chem. Inf. Comput. Sci..

[9]  Ann Tronde Pulmonary Drug Absorption : In vitro and in vivo investigations of drug absorption across the lung barrier and its relation to drug physicochemical properties , 2002 .

[10]  Hans Lennernäs,et al.  Drug Absorption from the Isolated Perfused Rat Lung–Correlations with Drug Physicochemical Properties and Epithelial Permeability , 2003, Journal of drug targeting.

[11]  Yung-Hsiang Chen,et al.  Semi-automatic high-throughput determination of plasma protein binding using a 96-well plate filtrate assembly and fast liquid chromatography-tandem mass spectrometry. , 2003, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[12]  F. Curriero,et al.  Expression of cytochromes P450 1A1 and 1B1 in human lung from smokers, non-smokers, and ex-smokers. , 2004, Toxicology and applied pharmacology.

[13]  Gerd Folkers,et al.  Pharmacokinetic Profiling in Drug Research , 2006 .

[14]  A. Wanner,et al.  Epithelial organic cation transporters ensure pH-dependent drug absorption in the airway. , 2007, American journal of respiratory cell and molecular biology.

[15]  Scott Boyer,et al.  Generation of in-silico cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 inhibition QSAR models , 2007, J. Comput. Aided Mol. Des..

[16]  Anders Tunek,et al.  High-throughput screening of drug-brain tissue binding and in silico prediction for assessment of central nervous system drug delivery. , 2007, Journal of medicinal chemistry.

[17]  Han van de Waterbeemd,et al.  QSAR Modeling Using Automatically Updating Correction Libraries: Application to a Human Plasma Protein Binding Model , 2007, J. Chem. Inf. Model..