Ocular pharmacokinetic/pharmacodynamic modeling for bunazosin after instillation into rabbits

Purpose. To develop a pharmacokinetic/pharmacodynamic (PK/PD) model for an alpha(1)-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.