Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

摘要

We have constructed a new ocular pharmacokinetic pharmacodynamic (PK/PD) model for anti-glaucomadrugs to describe ocular hypotensive effects on intraocular pressure (IOP) after instillation of a combination ofan a1-adrenergic antagonist, bunazosin, and a b -adrenergic antagonist, timolol, into rabbits. This model wasconstructed by the combination of two ocular PK/PD models for bunazosin and timolol by including aqueoushumor dynamics based on both action mechanisms. We also verified the reliability of this model by confirmingthe drug concentrations in aqueous humor and ocular hypotensive effects after instillation of the drug combination.The aqueous humor concentrations of timolol and bunazosin were determined by an HPLC, and ocular hypotensiveeffect-time profiles were measured using a telemetry system, which was able to record automaticallydetailed effects. The combined model could simulate the aqueous humor concentrations of both drugs and theadditive IOP-lowering effect after instillation of the combination using the MULTI (RUNGE) program andPK/PD parameters which were obtained from ocular hypotensive effects after instillation of bunazosin alone ortimolol alone. The theoretical concentration curves of both drugs in the aqueous humor and the theoretical ocularhypotensive effect curves almost agreed with both the observed concentrations and ocular hypotensive effectsafter instillation of the drug combination. These results indicate the reliability and usefulness of PK/PD modelingconsidering aqueous humor dynamics to predict IOP in multidrug therapy. This is the first study to develop aPK/PD model for multidrug therapy for the eye.