Use of drug kinetics in dermis to predict in vivo blood concentration after topical application.

PURPOSE

To use the drug kinetics in dermis to predict the in vivo blood concentration after topical administration.

METHODS

A two-step pharmacokinetic model was established. The first step was to calculate the drug input rate or flux from the skin to the systemic circulation using the drug kinetic parameters in dermis. These parameters include (a) distance over which the drug concentration declines by 50%, (b) drug concentration at the epidermal-dermal junction, and (c) minimal plateauing drug concentration in the muscle layer. These parameters were experimentally determined from the drug concentration-tissue depth profiles in the dermis, after the application of a topical dose of ddI (200 mg/kg) to rats. The second step was to use the drug input rate together with the systemic disposition pharmacokinetics of ddI in rats to predict the plasma concentration-time profiles. The model-predicted plasma concentration-time profiles were compared with the observed profiles, to determine the validity of the proposed pharmacokinetic model.

RESULTS

The observed steady state concentration (CSS) in individual animals (n = 6) deviated from the predicted values by 3 to 55% with 3 of 6 rats showing a < 15% deviation. The mean observed CSS of all animals deviated from the mean predicted values by less than 15%.

CONCLUSIONS

The close agreement between the observed and the model-predicted drug concentrations indicates that the systemic drug input can be calculated from the drug kinetics in the dermis.