Utility of hairless rats as a model for predicting transdermal pharmacokinetics in humans.

This study investigated the use of HWY hairless rats to predict human plasma concentrations of drugs following dermal application.Utilizing a deconvolution method, pharmacokinetic parameters (e.g. in vivo absorption rates) were determined for six transdermal drugs in hairless rats. Obtained data were used to simulate the human plasma concentration-time profiles of transdermal drugs, which were then compared with clinical data in humans. Because hairless rats have lower hair follicle density than do humans, the impact of hair follicle density on skin permeability to hydrophilic compounds was also evaluated.Pharmacokinetic parameters showed low intra-individual variability in hairless rats. Simulated concentration profiles for compounds with logarithm of the octanol-water partition coefficient exceeding two were comparable to clinical data, but simulated concentration profiles for hydrophilic compounds (i.e. bisoprolol and nicotine) at maximum concentration differed from clinical data by more than two-fold. Finally, in vitro permeability to bisoprolol and nicotine was higher in human skin than in hairless rat skin, but hair follicle plugging reduced human skin permeability.In vivo skin absorption data from HWY hairless rats help to predict human concentration profiles for lipophilic compounds. However, the data underestimate human absorption of hydrophilic compounds.

Utility of Göttingen minipigs for Prediction of Human Pharmacokinetic Profiles After Dermal Drug Application.

PURPOSE: Although Göttingen minipigs have been widely used for the evaluation of skin absorption, the correlation of minipig skin permeability with human skin absorption remains unclear. This study was designed to investigate the prediction of human plasma concentrations after dermal application of drug products using skin permeability data obtained from minipigs. METHODS: First, in vitro skin permeabilities of seven marketed transdermal drug products were evaluated in minipigs, and compared with in vitro human skin permeability data. Next, plasma concentration-time profiles in humans after dermal applications were simulated using the in vitro minipig skin permeability data. Finally, the in vitro-in vivo correlation of minipig skin permeability was assessed. RESULTS: The in vitro skin permeabilities in minipigs were correlated strongly with in vitro human skin permeability data for the same drug products, indicating the utility of minipig skin as an alternative to human skin for in vitro studies. The steady-state plasma concentration or the maximum concentration of drugs was within 2-fold of the clinical data. Bioavailability was approximately 3-fold lower than in vitro permeated fraction. CONCLUSIONS: Predictions using in vitro skin permeability data in Göttingen minipig skin can reproduce the human pharmacokinetic profile, although the prediction of in vivo skin absorption underestimates human absorption.