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

Abstract

1. 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.

2. 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.

3. Across the range of compounds tested, the prediction of human inhaled maximum concentration (C_max) 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 C_max from preclinical data ().

4. Administering as a dry powder formulation slowed the rat lung absorption rate of the least soluble compound (fluticasone propionate), impacting the prediction of C_max and MRT. This flags the potential for preclinical studies with dry powder formulations to positively influence predictive accuracy, although further studies with low solubility inhaled drugs are required to confirm this.

5. This study illustrates the value of preclinical assessment of PKs following administration to the lung, and provides a viable means of predicting the human PK profile for inhaled drugs.

Keywords::

• Lung
• absorption
• oratracheal
• inhaled
• pharmacokinetics
• prediction

Acknowledgements

We thank the many colleagues at Pfizer Global Research and Development (Sandwich, Kent, United Kingdom) who have generated data used in these analyses (Pharmacokinetics, Dynamics & Metabolism; Mark Bayliss, Phil Dalton, Jill Segelbacher. Pharm Sci; Jane Burrows, Jennifer Parnell. Biology; Garry Douglas. Clinical Research; John Davis, Fiona Macintyre and Jon Ward).

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.