Ocular pharmacokinetic/ pharmacodynamic modeling for bunazosin after instillation into rabbits.

PURPOSE: To develop a pharmacokinetic/pharmacodynamic (PK/PD) model for an alpha1-blocker (bunazosin) after instillation. The PK/PD model can predict both the drug concentrations in various ocular tissues and the hypotensive effect.

METHODS

Bunazosin concentrations were determined with High Performance Liquid Chromatography (HPLC) in tear fluid, the aqueous humor, cornea, and iris-ciliary body after instillation or ocular injection into the anterior chamber in rabbits. After instillation of bunazosin in rabbits, intraocular pressure (IOP) was also determined with a pneumatic tonometer. The PK/PD parameters were estimated by fitting the concentration-time profiles and the hypotensive effect-time profiles to the developed PK/PD models using the MULTI (RUNGE) program.

RESULTS

On the basis of the concentration-time profiles of bunazosin, a PK model, including seven compartments, was developed for examining the behavior of bunazosin after instillation. Then, two PK/ PD models for hypotensive effect of bunazosin were developed using an indirect response (model A) and the relationship between IOP and aqueous humor flow (model B). These models well described the concentration-time profiles and hypotensive effect-time profiles of bunazosin after instillation.

CONCLUSIONS

This study is the first trial to develop a PK/PD model for an antiglaucoma agent using an indirect response and the relationship between IOP and aqueous humor flow.