A new methodology for predicting human pharmacokinetics for inhaled drugs from oratracheal pharmacokinetic data in rats

Prediction of pharmacokinetic (PK) profile for inhaled drugs in humans provides valuable information to aid toxicology safety assessment, evaluate the potential for systemic accumulation on multiple dosing and enable an estimate for the clinical plasma assay requirements.The accuracy in prediction of inhaled human PK profiles for seven inhaled drugs or drug candidates (salmeterol, salbutamol, formoterol, fluticasone propionate, budesonide, CP-325366 and UK-432097) was assessed using rat oratracheal solution and dry powder PK data. The prediction methodology incorporates allometric scaling and mean residence time (MRT) principles with a two compartmental PK approach.Across the range of compounds tested, the prediction of human inhaled maximum concentration (Cmax) and MRT was within 2-fold for 5 of the 7 compounds, providing an accuracy of prediction similar to the current methodologies used to predict human oral Cmax from preclinical data ().Administering as a dry powder formulation slowed the rat lung abs...